The molecular basis of genetic disease

The molecular basis of genetic disease

Corinne D. Boehm and Haig H. Kazazian Jr

Department of Pediatrics, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA

Current Opinion in Biotechnology 1990, 1:180-187

Introduction

The spectrum of genetic disease is broad, extending from traits for which we are at the complete mercy of a change in one gene (single-gene disorders such as Huntington's disease, neurofibromatosis, and Duchenne muscular dystrophy) to those which are affected by the interaction of several genes as well as environmental influences (poly- genic or multifactorial traits such as schizophrenia, heart disease, and cancer). Initial efforts to identify genetic defects focused on the single-gene disorders; these are easier to identify because of their near absolute correlation with a certain health state. Genes focused on in the 1980s included those for a- and ]3-globin (defects producing thalassemia), Factors VIII and XI (hemophilia A and B, respectively), phenylalanine hydroxylase (associated with phenylketonuria), dystrophin (Duchenne/Becker muscular dystrophy) and low-density lipoprotein (LDL) receptors (hypercholesterolemia).

In Certain instances, the identity of a gene responsible for a given disorder was easy to predict because the affected protein was already known (globin defects, hemophilia A and B, and phenylketonuria): in other cases, the identification of the genetic defect preceded and allowed the identification of the affected protein, a process known as reverse genetics or positional gene cloning. For in- stance, it was the identification of mutations which produce Duchenne and Becker muscular dystrophy which led to the identification of dystrophin as the affected protein in these diseases. The application of reverse genetics to the discovery of disease-producing genes has relied heavily, although not exclusively, on gene mapping. This is the process of identifying the gross chromosomal location of a disease-producing gene by linkage analysis. Next, tedious examination of the target region is carried out for tell-tale signs of potentially important candidate genes. Sequences which might be considered for very close examination can be identified by a number of different strategies; these include identification of the following: HTF islands (Hpa II tiny fragments) containing many CpG dinucleotides, sequences conserved between species, an RNA transcript or stretches of DNA which give a long open reading frame. Ultimately, the mutations within the gene that causes the disease state need to be discovered.

The characterization of genetic defects is valuable in several respects. Firstly, it allows a better understanding of normal biological processes and identification of those sequences which are important for normal gene func- tion. Secondly, it leads us to a better understanding of particular diseases and enables us to devise more rational treatment for affected individuals. Thirdly, it allows more accurate diagnosis of a genetic disease, not only in affected individuals but also in asymptomatic carriers.

Following is a brief summary of the progress that has been made in the molecular analysis of human genetic disease between April 1989 and October 1990. We have not included new alleles found in genes already known to produce disease as this would produce a very long list and is beyond the scope of this review.

Linkage determinations

Charcot-Marie-Tooth disease For some time, linkage between a locus for the autosomal dominant hereditary motor and sensory neuropathy Charcot-Marie-Tooth disease (CMT) and the Puffy blood group on chromosome 1 has been known. How- ever, this linkage was not present in a large number of families with CMT disease. This particular puzzle was solved last year by identification of a separate locus for CMT disease to the pericentric region of chromosome 17 [1 ..]. Since that description, linkage of CMT to this latter locus has been described in an additional 15 CMT families [2,3]. CMT disease has now been subdivided clinically into CMTla (chromosome 17 locus) and CMTlb (chromosome 1 locus).

Spinal muscular atrophy The term spinal muscular atrophy encompasses a wide range of clinical disorders invoMng degeneration of an- terior horn cells of the spinal coM. Severity of disease ranges from the severe type I (Werdnig-Hoffman) to the milder chronic types II (intermediate Werdnig-Hoffman) and III (Kugelberg-Welander). Recently, two groups [4..,5 "'] have shown strong linkage of the locus responsible for types n and III disease to chromosome 5q (es-

Abbreviations CFTR--cystic fibrosis transmembrane regulator; CMT--Charcot-Marie-Tooth disease; LDL--Iow-density [ipoprotein;

NF-l--neurofibromatosis type 1; RFLP--restriction fragment length polymorphism.

180 (~) Current Biology Ltd ISSN 0958-1669

timated at 5q11-5q13) and one of these groups has also shown linkage of the severe type I to the same region [6"]. In total, 41 families were examined and in only two of these was the linkage between the disease locus and the 5q locus not documented. It is possible that disease was misdiagnosed in these families or perhaps they have a genetically distinct form of the disease.

The molecular basis of genetic disease Boehm and Kazazian 181

lies with two or three affected siblings produced a maximal lod score of 7.37 at a theta value of 0.00 with locus D5S72. Several genes with a possible role in this disease (including those for growth factors, growth factor receptors, and hormone receptors) are known to be located within this region. The gene for osteonectin lies more distally on chromosome 5.

Primary osteoarthritis In one large family, inheritance of the phenotype of primary osteoarthritis was linked to the COL2AI collagen gene on chromosome 12q [7"]. However, the nature of the defect producing this disease was not characterized, nor was it proven that mutation in the COL2M gene was the cause of disease.

Hereditary spherocytosis This autosomal dominant disease is characterized by ery- throcytes with a spherical (rather than biconcave) ap- pearance. Recently, this trait has been linked to the gene for ankyrin (lod score of + 3.63) in one large kindred with the disease [14].

Friedreich's ataxia The locus responsible for this autosomal recessive disease was described in 1988 as being near the centromeric region of chromosome 9 [8]. However, the question of genetic heterogeneity in this disease arose because of variation in the age of onset and clinical manifestations. Linkage analysis in 80 families from European, French- Canadian, Acadian, and Spanish populations with Friedre- ich's ataxia showed no instances of recombinations with the MCT112 locus on chromosome 9 [9"]. This analysis generated a maximal lod score of 25.09 at a recombina- tion fraction of 0.00. These data strongly suggest that either a single locus is responsible for the disease, or that one locus in predominatly involved. Thus, while this disease is clinically heterogeneous, it is almost always due to a gene or set of genes located near the centromere on chromosome 9.

Complete X-linked congenital stationary night blindness The X-linked form of complete stationary night blindness is associated with myopia; an autosomal dominant form of the disease is not. Tight linkage of this disease geno- type with a DNA marker at Xp11.3 was found in seven multigenerational families [ 10].

Malignant hyperthermia In three large Irish families with malignant hyperthermia as an autosomal dominant trait, linkage analysis localized the gene responsible to chromosome 19q12-13.2 [11 "]. A candidate gene for this disorder, the skeletal muscle ryanodine receptor, has recently been localized to chromosome 19cen-q13.2 and thus may have a role in this disorder [12].

Diastrophic dysplasia The locus for this relatively rare autosomal recessive form of osteochondrodysplasia has been localized to chromosome 5 using close linkage to three chromosome 5 restriction fragment length polymorphisms (RFLPs) [13 "']. Linkage analysis including 84 individuals from 13 fami-

Mutations identifying disease genes

Cystic fibrosis The gene for cystic fibrosis was cloned in mid-1989 by groups at the University of Michigan and The Hospital for Sick Children, Toronto [15" ' ,16" ' ,17" '] . The gene spans 250 kilobases and contains 27 exons. It encodes a member of the P-glycoprotein or ATP-binding transport super-family which is thought to be involved in chloride transport in epithelial cells and is referred to as the CFTR (cystic fibrosis transmembrane regulator) gene. A major mutation, deletion of three nucleotides eliminating phenylalanine at residue 508 in the first nucleotide-binding fold of the protein, accounts for roughly 70% of cases of cystic fibrosis worldwide. By September 1990s the cystic fibrosis genetics consortium had found about 60 other mutant alleles in various ethnic groups, no one of which accounts for more than 2% of cystic fibrosis genes. A mutation hot-spot has been found in the first of two nucleotide-binding folds in the CFTR protein [18]. Re- cendy, the gene has been transfected into epithelial cells from cystic fibrosis patients using viral vectors and this resulted in correction of the chloride transport defect in vitro [ 19 " ,20 "'].

Alport syndrome Three different alterations in the newly discovered X- linked COL4A5 gene have been identified in each of three families with X-linked Alport syndrome [21 ..,22 "-24"]. This collagen gene is a component of a basement membrane protein which had previously been implicated in Alport syndrome. The three alterations include an intragenic deletion, a single amino acid substitution (cysteine to serine) in a highly conserved non-collagenous domain of the protein, and an as yet uncharacterized mutation which manifests as an absence of a lightly hybridizing Taq I fragment on Southern blot analysis.

Wilms' tumor Two groups have isolated the same candidate gene for Wilms' tumor at chromosome 11p13 [25" ,26" ] . This

182 Mammalian gene studies

gene encodes a zinc-finger protein which is likely to be a transcription factor. The idea that this gene is important in the formation of Wilms' tumors is supported by several observations. Firstly, the gene is transcribed in a specific pattern in each of the developing kidneys, the organ in which the tumor arises, and genitalia, as well as in the tumor itself [27"]. Secondly, loss of the candidate gene or a part of it (25 base-pairs) has been associated with Wilms' tumors [28 °]. Interestingly, the deletion was not present in the germ line of the patient with the 25 bp intragenic deletion.

Neurofibromatosis type 1 Two groups have isolated and are characterizing the gene responsible for neurofibromatosis type 1 (NF-1) [29"-32 " ] . One group has named this gene NFILT and the other TBS (translocation break-point region). Several different mutations have been shown in the gene isolated by these groups, including: 17q translocation break- points within the gene; insertion of a 500 base Alu ele- ment within the gene that is associated with a sponta- neous case of NF-1; partial gene deletion; and nucleotide alterations within the gene (including one stop mutation). The gene has been shown to be active in many tissues including peripheral nerves, lymphoblasts, brain, spleen, and lung. Three other transcribed genes (one of which was originally a NF-1 candidate gene) lie within an intron of the NF-1 gene. All three are transcribed in the opposite orientation to the NF-1 gene. The encoded protein has significant homology with mammalian cytoplasmic GAP proteins which are involved in cell growth through interacting with proteins such as the ras gene product.

Familial hypertrophic cardiomyopathy This condition seems to result from a variety of molecular defects. One large kindred with hypertrophic cardiomyopathy as an autosomal dominant trait showed very tight linkage of the responsible gene (lod score of + 9.37 at a theta value of 0) to chromosome 14ql [33 "]. The gene encoding the [3 cardiac myosin heavy chain is a candidate because it is located on chromosome 14q. In another family with the disease a hybrid gene of the a/[3 cardiac myosin heavy chain was the molecular cause of the cardiomyopathy [34"] . Several sporadic cases were found to be the result of deletions within mitochondrial DNA [35].

Spondyloepiphyseal dysplasia Mutations within the COL2A1 collagen gene have been shown to be the cause of spondyloepiphyseal dysplasia in several instances. These include a 390 bp deletion of exon 48 (36 amino acids) which leaves the reading frame of the mRNA intact [36"]. In another case, a tandem duplication of 45 base pairs, also within exon 48, results in the addition of 15 amino acids [37]. Furthermore, altered electrophoretic mobility of the type II collagen of costal cartilage from 12 individuals with various forms of the

disease further implicates the COL2A1 gene as the locus responsible [38].

Xeroderma pigmentosum-B and Cockayne's syndrome Microinjection of mRNA from a functional DNA heli- case gene (the recently cloned ERCC-3 gene) corrected the DNA repair defect in cells from an individual with B complementation xeroderma pigmentosum who also has Cockayne's syndrome [39"] . However, this mRNA did not correct the defect in cells from the other seven complementation groups (A, C, D, E, F, G and H). The correction was accomplished following microinjection of ERCC-3 mRNA into homopolykaryons of cells from a patient with xeroderma pigmentosum-B. The ERCC- 3 mRNA restored the ability of the cell to perform ultraviolet-induced unscheduled DNA synthesis in vitro.

The mutation responsible for the corrected defect was an RNA-splicing defect in a consensus acceptor splice site which produced an mRNA with a four-base-pair insertion. This insertion destroys the open reading frame.

Marfan's syndrome Linkage of the Marfan's syndrome locus to chromosome 15q has been demonstrated in all of five informative Mar- fan's syndrome pedigrees which were examined [40-]. The maximal lod score was theta value 0.0 ( + / - 0 . 1 1 ) with the three chromosome 15 markers, D15S45, D15S29, and D15S25. The question of genetic heterogeneity in this disease remains to be explored. Recent functional studies have implicated the fibrillin gene as deficient in individuals with this disease [41 "] but the chromosomal location of this gene is not yet known.

Mechanisms producing genetic disease

Imprinting Prader-Willi and Angelman syndromes are clinically different diseases which result from deletions that are similar in location (chromosome 15) and extent. However, Prader-Willi syndrome results from inheritance of only maternal chromosome 15 sequences, whereas Angelman syndrome follows inheritance of only paternal chromosome 15 sequences. This suggests that the remaining (non-deleted) gene in an individual with Prader-Willi or Angelman syndrome has different functions depending on the parent from which it was inherited. This hypoth- esis has been further supported by the discovery of two cases of non-deletion Prader-Willi syndrome which were associated with maternal heterodisomy for the critical region of chromosome 15 (the inheritance by the affected individuals of both copies of the maternal chromosomes 15 and no copies of a paternal chromosome 15) [42.]. Both non-deletion and deletion cases of Prader-Willi syndrome seem to occur as a result of not inheriting paternal sequences from the critical region of chromosome 15. In contrast non-deletion Angelman syndrome has been seen following inheritance of critical regions from both


the mother and the father (Knoll et aL, A m J H u m Genet 1990, 47: Abs 883).

Somatic mosaicism Somatic mosaicism was recently documented in a man with mild osteogenesis imperfecta who had a son with a perinatal lethal form of the disease [43 "]. DNA from both individuals contained the same lethal single nucleotide change producing an amino acid substitution. However, polymerase chain reaction analysis showed varying preva- lence of this mutation in different cell types from the father (50% in fibroblasts, 27% in blood, and 37% in sperm) explaining his survival.

Mutations in nuclear DNA affecting mutations in mitochondrial DNA Several different mitochondrial myopathies (including Leder's hereditary optic neuropathy, infantile bilateral striatal necrosis, myoclonic epilepsy and ragged red mus- d e disease) result from mutations within mitochondrial DNA. These diseases are only inherited through the maternal lineage as mitochondria are only inherited from the mother. Deletions within mitochondrial DNA have also been found in individuals with mitochondrial myopathies who have a spectrum of neuromuscular symptoms. Re- cently a family with an autosomal dominant form of inherited mitochondrial myopathy was evaluated [44.]. Affected individuals in the family were found to have multiple, different mitochondrial DNA deletions, all of which affected the same region. A common 3' end of the break-point was identified within a 12 nucleotide cluster in all 19 deletions from mitochondrial DNA examined; these were from four affected family members. The break was in the D-loop region of mitochondrial DNA where protein-DNA interactions that affect mitochondrial DNA replication and transcription are thought to occur. Pre- sumably, a mutation within the nuclear DNA, which is inherited in this family as an autosomal dominant trait, has its pathological effect by promoting de novo deletions within mitochondrial DNA.

More than one phenotype caused by mutation at a single gene

Many examples exist of both genetic 'homogeneity' and genetic 'heterogeneity' within disease groups. The former are situations in which a single locus is apparently responsible for an inherited disease in all cases despite variation in clinical severity among them. In the latter, different loci are responsible for a seemingly identical clinical state in different individuals (these have also been called genocopies). Recently two examples of different diseases being caused by different mutations within the same gene, have been described.

In one family, a single nucleotide substitution at position 382 of the cz-subunit of the insulin receptor gene resulted

in insulin-resistant diabetes mellitus [45"]. Presumably post-translational modification was impaired resulting in fewer receptors on the cell surface. In another family, a single nucleotide substitution at position 233 in the cz- subunit resulted in leprechaunism [46.]. This mutation apparently lies within a region of the gene coding for a protein involved in transmitting the insulin-binding signal to the tyrosine kinase domain. In both of these cases, imprinting could not explain the different phenotypes because the situations involve a consanguineous mating in which the parents were both shown to be autosomal recessive carriers of the defect.

Mutations in the COL2A1 collagen gene which have previously been shown to be responsible for the Stickler syndrome [47] provide another example of this phenomenon. During the past year several instances of a mutation in this gene were also found to result in spondyloepiphyseal dysplasia [36",37]. Linkage studies suggest this gene is also affected in one family with osteoarthritis [7"].

Unequal sister chromatid exchange

Three instances have been described in which a dystrophin gene duplication was seen in a woman on a chromosome she had inherited from her father (as demonstrated by RFLP haplotype analysis) [48] which did not contain the duplication in the father's DNA. It is most likely that these duplications originated in the fathers of these women, by the mechanism of unequal sister chromatid exchange. Homologous chromosome recombina- tion would not be an explanation because males have only one X chromosome.

Susceptibility genes in multifactorial diseases

Multiple sclerosis A recent study analyzed the inheritance pattern of RFLP haplotypes of the T-cell receptor 13 chain gene in 40 families in which two or more siblings were affected with multiple sclerosis [49]. Within families, the affected sibling pairs showed a higher-than-expected rate of inheritance of identical haplotypes from their parents. This phenomenon was not seen in their unaffected siblings. In addition, particular specific T-cell receptor [3 chain haplotypes were over-represented among haplotypes being inherited by multiple sclerosis sibling pairs as compared with those parental haplotypes which were not inherited by the multiple sclerosis pairs. The data point to a locus (either the T-cell receptor [3 chain gene or a closely linked gene) which plays a role in an individual's susceptibility to multiple sclerosis. The authors calculated that this locus accounts for one sixth of the increased risk that siblings of individuals with multiple sclerosis have for developing the disease.


Non-syndromic cleft lip (with or without cleft palate)

In one recent study [50] the authors examined 12 RFLPs at five loci which are involved in palatogenesis in rodents. They compared the frequencies of allele types at these RFLPs in 80 individuals with non-syndromic cleft lip (with or without cleft palate) and in 102 controls. A significant difference in frequencies was observed for two RFLPs at the transforming growth factor-0t locus. This association implicates this gene, or a closely linked gene, in normal lip and palate development; it also suggests that there may be one allele type in the general population that produces a susceptibility to clefting and this allele is 'hitch- hiking' with a particular RFLP haplotype.

Heart disease It has been shown previously that increased levels of circulating LDL are a risk factor for coronary heart disease [51]. Mutations in the LDL receptor gene have been shown to account for the autosomal dominant form of hypercholesterolemia [52], a single gene disease which produces coronary artery disease. More recently [53], in- vestigators used an antibody to apolipoprotein B to meas- ure the relative amounts of LDL which were translated from maternally versus paternally derived apolipoprotein B alleles. Carriers of hypercholesterolemia in one family consistently under-expressed the form of apolipoprotein, which derived from inheritance of a particular apolipoprotein B gene, as a percentage of total serum LDL In non-carriers, this protein usually accounted for 33% of the total LDL protein but in six out of seven carriers this level was reduced to less than 15%. Thus, a variation in a gene's sequence, which is not in itself pathogenic, may have a role in an individual's susceptibility to a disease. Ultimate expression or lack of expression of a disease state will also depend on other genetic and environmental factors.

Summary

The pace of localization and characterization of genes affected in human genetic disorders is quickening. Many important genes were localized or characterized recently: genes for in cystic fibrosis, NF-2, Marfan's syndrome and xeroderma pigmentosum, to name a few. Also, in the past 15 months, the CFTR gene affected in cystic fibrosis has been isolated, the first disease gene to be isolated without use of previous cytogenetic clues, such as deletions or translocations in sporadic cases. Other examples should follow, although we have been disappointed to date by tile difficulties encour~tered in the isolation of Hunting- ton's disease gene which was localized a number of years ago to distal chromosome 4p [54]. It is still very difficult to isolate a disease gene without critical cytogenetic information. New improved techniques for finding the de- sired expressed sequences in a large cloned segment of human DNA are needed. Our ability to find mutant at-

leles of a given sequence has expanded greatly with the recent technical advances in denaturing gradient gel electrophoresis, chemical cleavage, and single-stranded con- formational electrophoresis.

One would predict that information derived from the human genome project will have a major impact upon the isolation of further disease genes. As whole regions of human chromosomes or indeed entire chromosomes are physically mapped and cloned as continuous, over- lapping YACs (yeast artificial chromosomes), isolation of disease genes will become easier and easier. The major challenge now lies not in the elucidation of the large number of single-gene disorders, but in the effort to find major genes involved in common diseases and congenital malformations and to sort out the different alleles of these genes. We look to the time, hopefully within 50 years, when most of the myriad disorders and congenital malformation syndromes seen in the genetics clinics of teaching hospitals can be accurately diagnosed by molecular methods. Prevention of recurrence of these disorders in subsequent offspring along with rational therapy should follow after their description in molecular terms.

Annotated references and recommended reading

• Of interest • . Of outstanding interest

1. VANCE JM, NICHOLSON GA, YAMAOKA LH, STAJICH J, STEWART "• CS, SPEER MC, HUNG WY, ROSES AD, BARKER D, PERICAK-VANCE

1V~ Linkage of Charcot -Mar ie-Tooth neuropa thy type l a to ch romosome 17. Exp Neurol 1989, 104:186~189.

The first report linking a form of CMT disease to a locus on chromosome 17. This accounted for the failure to link some cases of CMT disease to the previously known locus on chromosome 1.

2. MCALPINE PJ, FEASBY TE, HAHN AF, KOMARNICm L, JAMES S, GUY C, DIXON M, QAYYUM S, WRIGHT J, COOPIAND G, LEWIS M, KA1TA H, PHILIPPS S, WONG P, KOOPMAN W, COX DW, gEE WC: Localization of a locus for Charcot -Mar ie-Tooth neuropathy type l a (CMT1A) to ch romosome 17. Genomics 1990, 7:408415.

3. MIDDLETON-PRICE HR, HARDING AE, MONTEmO C, BERCIANO J, MALCOLM S: Linkage of hereditary motor and sensory neuropathy type 1 to the per icentromeric region of ch romosome 17. Am J Hum Genet 1990, 46:92-94.

4. BRZUSTOWICZ LM, LEHNER T, CASTILLA LH, PENCHASZADEH GK, • " WILHELMSEN KC, DANIELS R, DAVIES KE, LEPPERT M, ZITER F,

WOOD D, DUBOWlTZ V, ZERRES K, HAUSMANOWA-PERTRUSEWlCZ I, OTr J, MUNSAT TL, GILLIAM TC: Genetic mapping of chronic chi ldhood-onset spinal muscular atrophy to ch romosome 5q11.2-13.3. Nature 1990, 344:540-541.

See [5" ] .

5. MELKI J, ABDELHAK S, SHETH P, BACHELOT ME, BURLET P, • • MARCADET A, AICARDI J, BAROIS A, ARRIERE JP, FARDEAU M,

FONTAN D, PONSOT G, BILLETT T, ANGELINI C, BARBOSA C, FERRIERE G, LANZI G, OTrOLINI A, BABRON MC, COHEN D, HANAUER A, CLERGET-DARPOUX F, LATHROP M, MUNNICH A, FREZAL J: Gene for chronic proximal spinal muscular atro- phies maps to ch romosome 5q. Nature 1990, 344:767-768.

These two groups [4"•,5 ••] demonstrated a strong linkage between the disease locus for spinal muscular atrophy (types lI and III) and chromosome 5q.


6. GELIAM TC, BRZUSTOWlCZ LM, CASTILLA LH, LEHNER T, , PENCHASZADEH GK, DANIELS RJ, BYTH BC, KNOWLES J, HISLOP

JE, SHAPIRA Y, DUBOWITZ V, MUNSAT TL, OTT J, DAVIES KE: Genetic homogene i ty be tween acute and chronic forms of spinal muscular atrophy. Nature 1990, 345:823~325.

A report showing that the disease locus for spinal muscular atrophy type I (like types II and Ill) is also linked to chromosome 5q.

7. KNOWLTON RG, KATZENSTEIN PL, MOSKOWITZ RW, WEAVER EJ, • MALEMUD CJ, PATHRIA MN, JIMENEZ SA, PROCKOP DJ: Genet ic

linkage of a polymorphism in the type II procollagen gene (COL2A1) to primary osteoarthrit is associated wi th mild chondrodysplasia. N Engl J Med 1990, 322:526-530.

Although this report shows that inheritance of primary osteoatthritis in one large family is linked to the gene COI2A1, it does not show that the disease is caused by a defect in this gene.

8. CHAMBERLAIN S, SHAW J, ROWLAND A, WALLIS J, SOUTH S, NAKAMURA Y, YON GABALN A, FAREALL M, WILLIAMSON Pc Map- ping of muta t ion causing Friedreich's ataxia to h u m a n chro- m o s o m e 9. Nature 1988 334:248-250.

9. CHAMBERLAIN S, SHAW J, WALLIS J, ROWLAND A, CHOW L, FAREAL • M, KEATS B, RICHTER A, ROY M, MELANCON S, DEUFEL T,

BERCIANO J, WILI/AMSON Pc Genetic homogenei ty at the Friedreich ataxia locus on ch romosome 9. A m J Hum Genet 1989, 44:518-521.

Despite the clinical beterogeneity of this disease it is almost always due to a gene, or set of genes, near the centromere of chromosome 9.

10. MUSARELLA MA, WELEBER RG, MURPHEY WI-I, YOUNG RSL, ANSTON-CARTWRIGHT L, METS M, KRAFT SP, POLEMENO R, LITF M, WORTON RG: Assignment of the gene for comple te X-linked congenital stationary night bl indness (CSNB1) to Xpl l .3 . Genomics 1989, 5:727-737.

11. MCCAR~I-IY TV, HEALY JMS, HEFFRON JJA, LEHANE M, DEUFEL • T, LEHMANN-HORN F, FAREALL M, JOHNSON K: Localization of

the malignant hyper thermia susceptibility locus to h u m a n ch romosome 19q12-13.2. Nature 1990, 343:562-563.

The localization of the gene responsible for malignant hyperthermia to this site may implicate the gene for the skeletal muscle ryanodine receptor in this disorder, as it has also been localized to chromosome 19 cen~ll3.2.

12. MACLEr,~NAN DH, DUFF C, ZORZATO F, FUJI/ J, PH/ILIPS M, KORNELUK RG, FRODIS W, BRITT BA, WORTON RG: Ryanodine receptor gene is a candidate for predisposit ion to malignant hyperthermia. Nature 342:559-561.

13. HASTBACKA J, KAITILA I, SISTONEN P, DE LA CHAPELLE AA Diat- •" rophic dysplasia gene maps to the distal long arm of chro-

mosome 5. Proc Natl Acad Sci USA 1990, 87:8056-8059. This region of chromosome 5 includes several genes for growth factors, growth factor receptors and hormones which may have a role in this disease.

14. COSTA FF, AGRE P, WATIONS PC, WINKELMAN JC, TANG TK, JOHN , KM, Lux SE, FORGET BG: Linkage of dominant heredi tary

spherocytosis to the gene for the erythrocyte membrane- skeleton pro te in ankyrin. N EnglJMed 1990, 323:1046-1050.

In a large family, no crossing over was found between hereditary spherocytosis and the ankyrin gene.

15. ROMMENS JM, IANNUZZI MC, KEREM B-S, DRUMM ML, MELMER G, • " DEAN M, ROZMAHEL R, COLE JL, KENNEDY D, HIDAKA N, ZSIGA

M, BUCHWALD M, RIORDAN JR, TSUI L-C, COLLINS FS: Identifica- t ion of the cystic fibrosis gene: ch romosomes walking and jumping. Science 1989, 245:1059-1065.

See [17"'].

16. RIORDAN JR, ROMMENS JM, KEREM B-S, ALON N, ROZMAHEI R, "* GRZELCZAK Z, ZIELENSKI J, LOK S, PIAVSIC N, CHOU J-L, DRUMM

ML, IANNUZZa MC, COLLINS FS, TSUI L-C: Identification of the cystic fibrosis gene: cloning and characterization of com- p lementary DN& Science 1989, 245:1066-1073.

See [17"'].

17. KEREM B-S, ROMMENS JM, BUCHANAN JA, MARKIEWICZ D, Cox • " TK, CHAKRAVART1 A, BUCHWALD M, TsuI L-C: Identification of

the cystic fibrosis gene. Gene Anal Sci 1989, 245:1073-1079. These three papers [15" ' ,16" ,17 "°] describe the cloning of the gene responsible for cystic fibrosis.

18. CUTTING GR, KASCH LM, ROSENSTEIN BJ, ZIELENSKI J, TsuI L-C, ANTONARAV3S SE, KAZAZ~N HH JR: A cluster of cystic fibrosis mutat ions in the first nucleotide-binding fold of the cystic fibrosis conduc tance regulator protein. Nature 1990, 346:366-369.

19. DRUMM ML, POPE HA, CLIFF WH, ROMMENS JM, MARVIN SA, TSUI • " L-C, COLLINS FS, FRIZZELL RA, WILSON JM: Correction of the

cystic fibrosis defect in vitro by retrovirus media ted gene transfer. Cell 1990, 62:1227-1233.

See [20"] .

20. RICH DP, ANDERSON MP, GREGORY RJ, CHENG SH, PAUL S, "" JEFFERSON DM, MCCANN JD, KLINGER Iq~, SMITH AE, WELSH

MJ: Expression of cystic fibrosis t ransmembrane conduc- tance regulator corrects defective chloride channel regu- lation in cystic fibrosis airway epithelial cells. Nature 1990, 347:358-363.

The first report from two groups [ 1 9 " , 2 0 " ] that expression of the cystic fibrosis gene in vitro corrects the defect in epithelial cells from patients with the disease.

21. BARKER DF, HOSTIKKA SL, ZHOU J, CHOW LT, OLmHANT • * AR, GERKEN SC, GREGORY MC, SKOLNICK MH, ATIKIN

CL, TRYGGVASON K: Identification o f mutat ions in the COL4A5 collagen gene in Alport syndrome. Science 1990, 248:1224-1226.

See [24"]

22. HOSTIKKA SL, EDDY RE, BYERS MG, HOYHTYA M, SHOWS TB, • TRYGGVASON K: Identification of a distinct type IV collagen

a chain wi th restr icted kidney distribution and assignment of its gene to the locus of X chromosome-l inked Alport syndrome. Proc Natl Acad Sci USA 1990, 87:1606-1610.

See [24"].

23. MYERS JC, JONES TA, POHJOLAINEN E-R, KADRI AS, GODDARD aD, t SHEER D , SOLOMON E, PIHLAJANIEMI T: Molecular cloning of

a5(IV) collagen and ass ignment of the gene to the region of the X ch romosome containing the Alport syndrome locus. Am J Hum Genet 1990, 46:1024=1033.

See [24"].

24. FLINTER FA, ABBS S, BOBROW M: Localization of the gene for classic Alport syndrome. Genomics 1989, 4:335-338.

The above four papers [21°%22"-24 "] describe the association between three distinct mutations in the collagen gene COL4A5 and Alport syndrome in three families.

25. CALL KM, GLASER T, ITO CY, BUCKLER AJ, PELLETIER J, HABER DA, "" ROSE EA, KRAL A, YEGER H, LEWIS WH, JONES C, HOUSMAN DE:

Isolation and characterization of a zinc finger polypeptide gene at the h u m a n ch romosome 11 Wilms' tumor locus. Cell 1990, 60:509-520.

See [26..].

26. GESSLER M, POUSTKA A, CAVENEE W, NEVE RL, OP, K~ SH, BRUNS " GAP: Homozygous delet ion in Wilms tumours of a zinc-fin-

ger gene identified by ch romosome jumping. Nature 1990, 343:774-778.

The above two papers [25°%26 ' ' ] report the isolation of a candidate gene for Wilms' tumour. It encodes a zinc-finger protein which is likely to be a transcription factor.

27. PRITCHARD-JONES K, FLEMING S, DAVIDSON D, BICKMORE W, • PORTEOUS D, GOSDEN C, BARD J, BUCKLER A, PELLETIER J,

HOUSMAN D, VAN lq~YNINGEN V, HASTIE N: The candidate Wilms's t umour gene is involved in genitourinary development . Nature 1990, 346:194-197.

See [28*]

28. HABER DA, BUCKLER AJ, GLASER T, CALL KM, PELLETIER J, SOHN , RL, DOUGLASS EC, HOUSMAN DE: An internal delet ion wi th in


an l l p 1 3 zinc finger gene contr ibutes to the development of Wilms' tumor. Cell 1990, 61:1257-1269.

A 25bp deletion in the candidate gene described above [27%28.] is found in a Wilms tumor, but not in the patient's germline DNA. This is consistent with inactivation of a tumor suppressor gene.

29. VISKOCHIL D, BUCHBERG AM, Xo G, CAWTHON RM, STEVENS *" J, WOLFF RK, CULVER M, CAREY JC, COPEI~ND NG, JENKINS

NA, WHITE R, O'CONNELL P: Deletions and a translocation interrupt a cloned gene at the neurofihromatosis type 1 locus. Cell 1990, 62:187-192.

See [32 °. ]

30. WALLACE MR, DOUGLAS MA, ANDERSEN LB, LETCHER R, ODEH "" HM, SAUL1NO AM, FOUNTAIN JW, BRERETON A, NICHOLSON J,

MYrCHELL AL, BROWNSTEIN BH, COLLINS FS: Type 1 neurofibromatosis gene: identification of a large transcript d isrupted in three NF1 patients. Science 1990, 249:181-186.

See [32"*]

31. CAWTHON RM, WEISS R, XU G, VISKOCHIL D, CULVER M, STEVENS ' ' J, ROBERTSON M, GESTELAND R, DUNN D, O'CONNELL P, WHITE

R: A major s egmen t o f the neurofibromatosis type 1 gene: cDNA sequence, genomic s t ruc ture and point mutations. Cell 1990, 62;193-201.

See [32" ]

32. Xu G, O'CONNELL P, VISKOCHIL D, CAWTHON R, ROBERTSON M, "" CULVER M, DUNN D, STEVENS J, GESTELAND R, WHITE R, WEISS

R: The neurofibromatosis type 1 gene encodes a protein related to GAP. Cell 1990, 62:599-608.

The above four papers [ 2 9 " - 3 2 " ] describe the isolation of the gene responsible for NF-1. Various mutations within the gene have been associated with disease. The encoded protein shows significant homology with mammalian cytoplasmic GAP proteins.

33. JARCHO JA, MCKENNA W, PARE PJA, SOLOMON SD, HOLCOMBE * RF, DICKIE S, LEVI T, DONIS-KELLER H, SEIDMAN JG, SEIDMAN CE:

Mapping a gene for familial hyper t rophic cardiomyopathy to ch romosome 14q. N EngIJ Med 1989, 321:1372 1378.

One large kindred with hypertrophic cardiomyopathy showed very tight linkage to the chromosome 14ql. Because of its similar location, the gene encoding 13 cardiac myosin heavy chain is a possible candidate gene for the disease.

34. TANIGAWA G, JARCHO JA, KASS S, SOLOMON SD, VOSBERG I-L "" P, SEIDMAN JG, SEIDMAN CE: A molecular basis for familial

hyper t rophic cardiomyopathy: an cc/13 cardiac myosin heavy chain hybrid gene. Cell 1990,62:991-998.

In this family with hypertrophic myopathy, the disease was caused by a hybrid gene of the c~/[3 cardiac myosin heavy chain.

35. OZAWA T, TANAKA M, SUG1YAMA S, ITATTOPd K, Iwo T, OHNO K, TAKAHASHI A, SATO W, TAKADA G, MAYUMI B, YAMAMOTO K, ADACHI K, KOGA Y, TOSHIMA H: Multiple mitochondrial DNA delet ions exist in cardiomyocytes of pat ients wi th hyper t rophic or dilated cardiomyopathy. Biocbem Biopbys Res Commun 1990, 170:830-836.

36. LEE B, VISSING H, RAMIREZ F, ROGERS D, RIMOIN D: ldentifica- , t ion o f the molecular defect in a family wi th spondyloepi-

physeal dysplasi,'L Science 1989, 244:978-980. In several cases, this disease results from mutations within the COL2A1 collagen gene. These include a 390 bp deletion of exon 48 which leaves the reading frame intact.

37. TILLER GE, RIMOIN DL, MURRAY LW, COHN DH: Tandem dupli- cat ion wi th in a type II collagen gene (COL2AI) exon in an individual wi th spondyloepiphyseal dysplasia. Proc Natl Acad Sci USA 1990, 87:3889-3893.

38. MURRAY LW, BAUTISTA J, JAMES PL, RIMOIN DL: Type II collagen defects in the chondrodysplasias I spondyloepiphyseal dysplasia. Am J Hum Genet 1989, 45:5-15.

39. WEEDA G, VAN HAM RCA, VERMEULEN W, BOOTSMA D, VAN DER "" EB AJ, HOEIJMAKERS JHJ: A p r e sumed DNA hellcase encoded

by ERCC-3 is involved in the h u m a n repair disorders xeroderma p igmen tosum and Cockayne's syndrome. Cell 1990, 62:777-791.

The microinjection of mRNA encoding the ERCC-3 protein corrected the DNA repair defect in cells from a patient with xeroderma pigrnen- tosum in vitro.

40. KAINULAINEN K, PULKKINEN L, SALOLAINEN A, KAITILA I, PELTONEN . L: Location on ch romosome 15 of the gene defect causing

Marfan syndrome. N Engl J Med 1990, 323:935-939. The locus for disease has been linked to chromosome 15q in five out of five informative pedigrees.

41. HOtEISTER DW, GODFREY M, SAKAI LY, PYERITZ RE: Immuno- . histologic abnormalities of the microfibrillar-fiber sys tem in

the Marfan syndrome. N EnglJ Med 1990, 323:152-159. This study implicates a defect in the fibrillin gene in this disease although the chromosomal location is not yet known.

42. NICHOLLS RD, KNOLL JHM, BUTTER MG, KARAM S, LALANDE , M: Genetic imprint ing sugges ted by maternal heterodis-

omy in non-delet ion Prader-Willi syndrome. Nature 1989, 342:281-285.

Two cases of non-deletion Prader-Willi syndrome which were associated with the inheritance of both copies of the mammal chromosome 15 and no copies of the paternal homologue. This supports the hypoth- esis that the gene responsible has different functions on the paternaUy and maternally derived chromosome 15.

43. WALLIS GA, STARMAN BJ, ZINN AB, BYERS PH: Variable ex- . pression of os teogenesis imperfecta in a nuclear family is

explained by somatic mosalcism for a lethal point mutation in the aI (1) gene (COL1A1) of type 1 collagen in a parent. Am J Hum Genet 1990, 46:1034-1040.

The survival of a father with a lethal point mutation for this disease (which killed his son perinatally) was shown to be the result of somatic mosaicism. Only a portion of his cells contained the mutation which had arisen during embroyogenesis.

44. ZEVlANI M, SERVlDEI S, GELLERA C, BERTINI E, DIMAURO S, . DIDONATO S: An autosomal dominant disorder wi th multi-

ple delet ions o f mitochondrial DNA starting at the D-loop region. Nature 1989, 339:309--311.

This study suggests that a mutation within nuclear DNA, which is inherited as an autosomal dominant trait, can promote de novo deletions within mitochondrial DNA.

45. ACClLt D, FRAPIER C, MOSTHAF L, MCKEON C, ELBEIN SC, . PERMUTF MA, RAMOS E, LANDER E, ULLRICH A, TAYLOR SL: A

muta t ion in the insulin receptor gene that impairs transport of the receptor to the plasma membrane and causes insulin-resistant diabetes. EMBO J 1989, 8:2509-2518.

See [46"]

46. KLINKHAMER MP, GOREN NA, VAN DER ZON GCM, LINDHOUT D, . SANDKUYL LA, KRANS HMJ, MOLLER W, MAASSEN J& A leucine-

to-proline muta t ion in the insulin receptor in a family wi th insulin resistance. EMBO J 1989, 8:2503-2507.

The two papers above [45", 46"] demonstrate the principle that different genetic diseases can be produced by different mutations in the same gene.

47. ERANCOMANO CA, LIEBERFARB RM. HmOSE T, MAUMENEE I, STREETEN EA, MEYERS DA, PYERITZ RE: The Stickler syndrome: evidence for close linkage to the structural gene for type II collagen. Genomics 1987 1:293-296.

48. Hu X, BURGHES AHM, BULMAN DE, RAY PN, WORTON RG: Evi- dence for muta t ion by unequal sister chromat id exchanges in the D u c h e n n e muscular dystrophy gene. Am J Hum Genet 1989, 44:855-4363.

49. SEBOUN E, ROBINSON /VIA, DOOLITI'LE TH, ClUtLA TA, KINDT TJ, HAUSER SL: A susceptibility locus for multiple sclerosis is l inked to the T cell receptor 13 chain complex. Cell 1989, 57:1095--1100.

50. ARDINGER I-IH, BUETOW KH, BELL GI, BARDACH J, VANDENMARK DR, MURRAY JC: Association of genet ic variation of the trans-

The molecular basis of genetic disease Boehm a n d Kazazian 187

forming growth factor-alpha gene with cleft lip and palate. Am J H u m Genet 1989, 45:348-353.

51. HERBERT PN, ASSMANN G, GOTrO AM JR, FREDRICKSON DS: In The metabolic basis of inherited disease edited by Stanbury

JB, Wyngaarden JB, Fredrickson DS, Goldstein JL, Brown MD. New York: McGraw-Hill, 1983, 5, pp 589-651.

52. BROWN MS, GOLDSTEIN JL: A receptor-mediated pathway for cholesterol homeostasis. Science 1986, 232:34-47

53.

54.

GAVISH D, BRINTON EA, BRESLOW JL: Heritable aUele-specific differences in amounts of apoB and low-density lipopro- reins in plasma. Science 1989, 244:72-76.

GUSELLA JF, WEXLER NS, CONNOULLY PM, NAYLOR SL, ANDERSON MA, TANZI RE, WATKINS PC, OTTINA K, WALLACE MR, SAKAGUCHI AY, YOUNG AB, SHOULSTON I, BONILLA E, MARTIN JB: A poly- morphic DNA marker genetically linked to Huntington's disease. Nature, 1989 306:234-238.

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The molecular basis of genetic disease