Defective Myosin Genes in Mutant Mice and Human Diseases

Cong. Anom., 39: 107-1 16,1999

Review

Defective Myosin Genes in Mutant Mice and Human Diseases

Satoshi YONEZAWA’, Shigeo MASAK12, Takao ONO’, Atsuko HANAI’,

Takashi KAGEYAMA4, Akihiko MORIYAMA’ and Shinichi SONTA’ Departments of Embryology’, Biochemistry’ and Genetics’, Institute for Developmental Research, Aichi Human Service Center, Kasugai, Aichi 480-0392, Japan JPrimate Research Institute, Kyoto University, Inuyama, Aichi 484-8506, Japan ’Division of Biomolecular Science, Institute of Natural Sciences, Nagoya City University, Nagoya, Aichi 467-8501, Japan

ABSTRACT Myosins are highly divergent actin-based molecular motors. In five of eight classes expressed in mammals, defects in genes have been identified in mutant mice and/or

human diseases. A mutated myosin 11-7 gene is one of the causes of human familial

hypertrophic cardiomyopathy (FHC). The defective myosin Va gene is responsible for Griscelli disease, which is characterized by partial albinism and immunodeficiency, while in

its mouse homologue coat color dilution is seen with or without neurological defects. There are three classes of myosins, VI, VII and XV, that are essential in the inner ear function. In

humans, mutations in the VIIa gene are associated with three deafness-related diseases, Usher lB/DFNB2/DFNAll, providing the first example of exhibition of recessive- and

dominant-inherited disorders by different mutations in a single myosin gene. There are variations in phenotype between human diseases and their mouse models, which

appear to be explicable on the basis of differences in tissue expression patterns of the given

myosin between mouse and man. In FHC and Usher IBDFNB2DFNA11, a wide spectrum of clinical symptoms are observed. Evidence has accumulated suggesting that the more functionally important the mutation site of the molecule, the more serious and severe the symptoms, although involvement of additional factors such as modifier genes and genetic

background can not be ruled out. Molecular genetic analyses of a variety of dilute alleles in

mice have greatly facilitated our understanding of genotype-phenotype correlations, including information about structurally and functionally important domains of the myosin Va protein and cell-type-specific functions of different isoforms produced by alternative splicing.

Received September 6, 1999 Presented at the Symposium “Human Congenital Anomalies and Homologous Animal Models” at the 39th Annual Meeting of the Japanese Teratology Society, Kagoshima, Japan on July 14. 1999.

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108 S. Yonezawa et al.

Myosin Families Expressed in Mammals

The myosin superfamily is a diverse set of actin-based molecular motors, which are involved in a variety of cellular events such as contraction, cytokinesis, vesicle-trafficking, phagocytosis, locomotion and signal transduction (Sellers and Goodson, 1995; Mooseker and Cheney, 1995; Mermall et al., 1998). In mammals there exist several dozens of myosin genes belonging to eight families or classes (I, 11, V, VI, VII, IX, X, XV; Fig. 1) . All myosin proteins consist of three distinct regions: the head or motor domain containing ATP- and actin-binding sites; the neck or regulatory domain containing one or more myosin light chain- and/or calmodulin-binding sites; and the tail which is the site of interaction with other cellular components. The classification of myosins is based on structural variation in the relatively conserved head region. The three- dimensional model of the head domain of chicken skeletal muscle myosin which has been constructed based on the X-ray crystallographic analysis (Rayment et al., 1993a,b) makes it possible, though to a limited extent, to examine the structural consequences of mutations identified in the heads of other myosins. In the tail region various family-specific structures, believed to define the specialized function of a given myosin, have been identified.

Mutations of myosin genes in five classes, 11, V, VI, VII and XV, have now been identified in mutant mice and/or human diseases (Table 1). The VII and XV classes were newly identified in the search for responsible genes in deafness mutant mice. At least three classes of myosins, VI, VII and XV, are essential for the structural integrity of the inner ear (Hasson et al., 1997; Probst et al., 1998). Extensive screening for the presence of mutations in 11-7 and VIIa genes has been carried out for human familial hypertrophic cardiomyopathy and Usher Type 1B syndrome, respectively. In this review, we describe similarities and differences in phenotypes of myosin-associated human diseases and their mouse homologues, and present recent findings on genotype- phenotype correlations.

Head Neck Tail I u

Coiled-coil domain

MyTH4 domain 100 a.a.

1-

I1 d Talin-like domain

f3 Cys-rich domain

v IIv/////A Ki L4 I md GAP domain

VI _____. PH domain

IX - 14 V A I

x xv - R'T 1

Fig. 1 Schematic illustration of the structures of myosins expressed in mammals. The motor head domains are conserved, but the tail structures which are characteristic of a given myosin class are very diverse. In the neck region, 1 to 6 IQ repeats (IQxxxRGxxxRK) that are myosin light chain- and/or calmodulin-binding domains are recognized. Boxes in the tail regions represent different domains predicted by sequence homology: MyTH4 domain, myosin tail homology 4 domain; Cys-rich domain, cysteine-rich Zn"-binding domain; GAP domain, rho GTPase-activating protein domain: PH domain, pleckstrin homology domain. For further details, see the text.

Defective myosin genes in mice and humans 109

Table 1 Mutant mice and human diseases associated with defective myosin genes myosin mutant mouse human disease

class I1 aMHC4"' mouse (dominant) FHC (hypertrophic cardiomyopathy: dominant)

atrial and ventricular hypertrophy ventricular hypertrophy V dilute mouse (d : recessive) Griscelli syndrome (recessive)

coat color dilution silvery or grey hair neurological impairment immunodeficiency

neurological impairment VI Snell's waltzer mouse (sv : recessive)

deafness vestibular dysfunction

VII shaker-1 mouse (sh-1 : recessive ) Usher syndrome (recessive) deafness deafness vestibular dysfunction vestibular dysfunction

retinitis pigmentosa DFNB? (recessive)

deafness DFNAll (dominant)

deafness XV shaker-2 mouse (sh-2 : recessive) DFNB3 (recessive)

deafness deafness vestibular dysfunction

Myosin 11-7 Mutations (Human Familial Hypertrophic Cardiomyopathy)

Class 11, referred to as 'conventional-type' myosins, includes 6 skeletal-type, 2 cardiac-type and 2 nonmuscle-type isoforms, all characterized by a coiled-coil structure throughout the tail region. Through the coiled-coil region myosin 11s can self-associate to form two-headed motors. Of the class I1 isoforms, myosin II-

7 (cardiac p-isoform) is the only myosin species identified as associated with human disease.

Familial hypertrophic cardiomyopathy (FHC) is characterized by asymmetric ventricular hypertrophy with a

wide spectrum of clinical symptoms. It can be caused by mutations in at least 7 genes encoding proteins of the myofibrillar apparatus: cardiac troponin T, cardiac troponin I, a-tropomyosin, ventricular myosin essential light

chain, ventricular myosin regulatory light chain, cardiac myosin binding protein C and the myosin 11-7 isoform.

Over 40 missense mutations have been identified in the myosin 11-7 gene in association with the heart disorder (for review, Bonne et al., 1998; Cuda et al., 1998). The disease is transmitted as an autosomal-

dominant trait, and interestingly the mutations are all of missense type and almost restricted to the motor head

region. It is possible that most mutations occurring in the coiled-coil tail region are dominant-lethal. Myosin II- 7 mutations leading to FHC do not appear to grossly alter protein stability (Straceski et al., 1994). In addition, a

depressed actin-activated MgATPase activity (Sweeney, et al., 1994) and a reduced velocity in movement along actin filaments (Straceski et al, 1994) have been observed for mutated myosins. Therefore, it is generally accepted that the formation of stable and dysfunctional 11-7 heterodimers underlies the expression of FHC.

Indeed, a nonsense mutation shows no dominant phenotype of FHC (Nishi et al., 1995).


Clinical expression of FHC is markedly heterogeneous. This may be explained by the recent finding that mutations at functionally important sites of myosin 11-7 molecule are associated with high penetrance and early expression of disease (Rayment et al., 1995; Hwang et al., 1998) .

The aMHCm3 mouse strain, generated through introduction by the ‘hit and run’ technique of Arg403Gln mutation in the head region of myosin 11-6 isoform (cardiac a-isoform), serves as an animal model of FHC (Geisterfer-Lowrance et al., 1996). Heterozygous (403/+) mice bearing the missense mutation exhibit typical histopathologic features, while homozygous animals die by postnatal day 8, due to a fulminant dilated cardiomyopathy characterized by myocyte dysfunction and loss (Fatkin et al., 1999).

Finally, knockout mice for isoform B of nonmuscle-type myosin die by the first day of birth, due to structural cardiac defects (Tullio et al., 1997). Although the nonmuscle-type B isoform is expressed in a variety of cells, the main target of deterioration appears to be the cardiac tissue. No abnormalities are observed in B’” heterozygotes. The gene for the B isoform maps to human chr. 1 7 ~ 1 3 , but it is not known whether the gene is disease-associated in man.

Myosin Va Mutations (Dilute Mouse and Human Griscelli Syndrome)

Isoform a of myosin class V (Va) is a typical vesicle-trafficking, two-headed molecule, playing a part in transport of melanosomes in melanocytes, and of synaptic vesicles and sER in the brain. The COOH-terminal

globular region of the myosin Va tail has convincingly been demonstrated to bind directly with synaptobrevin I1 and synaptophysin, both of which are membrane proteins of synaptic vesicles (Prekeris and Terrian.1997). The tail region can also bind membrane proteins of melanosomes (Wu et al., 1997) and of sER in cerebellar Purkinje cells (Dekker-Ohno et al., 1996; Takagishi et al., 1996). Three coiled-coil domains in the tail are involved in the formation of functional Va homodimers.

Mutations of the mouse Va gene in what is known as the dilute (d) locus cause, when homozygous, coat color dilution, with or without neurological impairment (Strobe1 et al., 1990; Mercer et al., 1991). Although myosin Va is widely expressed in tissues, the pathologic features in mutant mice are melanocyte- and nervous tissue-specific. Earlier studies have indicated the presence of many d alleles exhibiting different phenotypes from weak to strong dilution for coat color, and from non-defective to lethal for the neurological impairment, while functionally null mutations apparently lead to lethality.

Recent studies by Jenkins and collaborators on genotype-phenotype correlations revealed that differences in d phenotype are elicited through complicated phenomena concerning the stability of affected mRNA and protein, and the direct and indirect effects of a given mutation on structural and functional domains (Huang et al., 1998a,b). With splice site mutations, abnormal splicing events can yield protein species that are either less functional or functionally null. Furthermore, altered phenotypes can be exhibited in association with mutations in tissue-specific alternative splicing sites. Detailed analysis of d alleles in mice has thus given valuable information about genotype-phenotype correlations.

With Griscelli disease, a human homologue of d mutations, the patients are afflicted by profound immunodeficiency in addition to exhibiting silvery or grey hair (Griscelli et al. 1978; Klein et al., 1994). Myosin Va mutations have been identified in two consanguineous patients: one has a nonsense mutation at a head-neck junction site, and the other has a missense mutation in the tail (Pastural et al., 1997). The patients are homozygous for the respective mutations, and neurological impairment is also observed for the patient carrying


the nonsense mutation (Pastural et al., 1997). The question as to why d alteration in the mouse is not associated with immunodeficiency remains to be answered. It appears possible that another myosin isoforni works in murine lymphocytes in place of the Va isoform.

Myosin VI Mutations (Snell’s Waltzer Mouse)

Myosin VI is a ubiquitous protein, having a coiled-coil domain and a unique COOH-terminal in the tail. Only a single isoform is known in this group. Immunocytochemical studies suggest that myosin VI plays a role in membrane traffic for secretory and endocytic pathways (Hasson and Mooseker, 1994; Buss et al. 1998), but no evidence has been obtained for direct interaction of its tail with distinct cellular components.

In mice, a defective myosin VI gene is responsible for Snell’s waltzer (m), a mutant strain having recessive- inherited inner ear defects (Avraham et al. 1995). Two different mutations in the myosin VI gene have been identified in sv alleles, within a dilute (+short ear ( se ) region of chr. 9. Its syntenic human region is chr. 15q21. It is of interest to point out that a recessive nonsyndromic deafness gene, DFNB16, maps around this site.

Myosin VIIa Mutations (Shaker-1 Mouse and Human Usher 1BI DFNB2mFNA11)

The myosin VIIa isoform was first identified as a deafness-associated myosin in mice and humans (Gibson et al., 1995; Weil et al., 1995). In the tail region, it has one coiled-coil domain, two myosin tail homology 4 (MyTH4) domains and two talin homology domains (Chen et al., 1996). MyTH4 domains are recognized as

being homologous structures among classes IV (nonmammalian), VII, X, XI1 (nonmammalian) and XV, but their functional importance has not yet been defined. The talin-like domain is homologous to the NH2-terminal of talin, a component of the cell adhesion complex, and considered to be a plasma membrane-associating site. Myosin VIIa is almost ubiquitous, like many other myosins, but in the liver VIIa transcripts are not detectable.

Now it is known that VIIa mutations are the cause of three different deafness-related diseases, Usher Type IB, DFNB2 and DFNA11. Usher 1B is a recessive, syndromic disorder characterized by deafness, vestibular dysfunction and retinitis pigmentosa, while DFNB2 and DFNAl 1 are recessive- and dominant-inherited nonsyndromic deafness disorders, respectively.

The Usher 1B syndrome is the most frequent cause of human deaf-blindness. Worldwide screening for the presence of mutations in the myosin VIIa gene of Usher patients has been carried out, and to date over 40 alterations have been identified as disease-associated (Weston et al., 1996; Levy et al., 1997; Adato et al., 1997; Hasson, 1997; Janecke et al., 1999). These include missense, nonsense and splice site mutations, deletions and insertions throughout the gene, except for within the coiled-coil domain (see below). Usher 1B patients are usually homozygotes or compound heterozygotes, but in some cases only simple heterozygous mutations have been identified. Most probably, this indicates that a mutation is present on the other allele in an unscreened region of the gene.

In DFNB2 patients four different mutations have been identified along the myosin VIIa gene: two different homozygous missense mutations in consanguineous patients and one compound heterozygous case with nonsense and splice site mutations (Weil et al., 1997; Liu et al., 1997a). In some patients vestibular dysfunction is observable, but DFNB2 can be clearly distinguished from Usher 1B by the absence of blindness. The positions of mutations found in DFNB2 patients are different from those identified in Usher 1B patients, but it is


difficult to simply assess their positional effects with reference to phenotypic difference. An alternative explanation for these latter is that different modulation by additional factors, such as modifier genes and genetic background, is involved.

Recently it has been shown that a mutation in the coiled-coil domain of VIIa leads to dominant-inherited deafness: an in-frame 9bp deletion in myosin VIIa exon 22, which results in deletion of three amino acids in the coiled-coil domain of myosin VIIa tail, has been identified in all of eight DFNAl1 patients in a single family (Liu et al., 1997b). All patients are heterozygous (Tamagawa et al., 1996). By analogy with the class 11-7 isoforrn case, this type of mutation may result in formation of stable and dysfunctional heterodimers to exert its 'dominant negative' effect.

As animal models of these deafness diseases, there are many with shaker-1 alleles, which greatly contributed to the identification of Usher 1B gene. Unlike the case with Usher 1B patients, however, no shaker-1 allele is linked to gross signs of retinal degeneration. It is accepted that the difference is attributable to variation in myosin VIIa expression in retinal tissue between humans and mice. It is detectable in both the pigment epithelium and the photoreceptor cells in the human retina, and in the pigment epithelium alone in the mouse (Hasson et al., 1995). Apparently, this explanation is applicable to the phenotypic difference between humans and mice, but not between Usher 1B and DFNB2 patients. The levels of myosin VIIa mRNA with shaker-1 alleles are all in the normal range, but the protein amounts greatly differ, from wild-type levels in original shaker-I mice to 1% of normal levels with ~ h a k e r - 1 ~ ~ ~ ~ ~ " and shuker-PmB alleles (Mburu et al., 1997). It is important to note that ~ k a k e r - 1 ~ ~ ~ ~ ~ ~ heterozygotes, which exhibit a normal phenotype, show about a half the normal level of myosin VIIa protein, suggesting that defective VIIa protein is degraded before the formation of functional dimers.

Myosin XV Mutations (Shaker-2 Mouse and Human DFNB3)

Search for the responsible gene in the shaker-2 deafness mouse and its possible syntenic human homologue, DFNB3, gave a third example of an association of inner ear dysfunction with a defective myosin gene (Probst et

al., 1998; Wang et al., 1998). A newly identified myosin, XV, has one MyTH4 domain and one talin homology domain in the tail, but lacks a coiled-coil domain, suggesting that it is a monomeric protein. Although myosin XV is expressed abundantly in the brain, no neurological defects are observed in either human patients or mutant mice. It has been considered that myosin XV may play a part in the maintenance of actin organization in the sensory epithelium of the inner ear.

In shaker-:! mice, a missense mutation has been identified in a conserved region of the myosin XV head. In addition, homozygous missense or nonsense mutations in the myosin XV gene have been identified in DFNB3 patients from two consanguineous families and one nuclear family. DFNB3 is nonsyndromic, but we do not know whether participation of myosin XV in vestibular signaling pathways differs between mouse and man, because it is unclear if the DFNB3 patients maintain a normal vestibular function.

Other Myosins

There is no report of any association of defective myosin genes of classes I, IX or X with human diseases. Class I is a large family including at least 7 isofoms (Hasson et al., 1996). Some members have an SH3 domain

Defective myosin genes in mice and humans 1 I3

in the tail, and all are single-headed and monomeric. It has been suggested that they are involved in a variety of

membrane-based phenomena, such as endocytosis, exocytosis and lysosome transport (Mermall et al., 1998). Class IX myosins are unique, in that they have an NHz-terminal extension in the head region, and a rho-

GTPase activating domain and a cysteine-rich Zn"-binding site in the tail region (Reinhard et a]., 1995; Post et

al., 1998; Chieregatti et al., 1998). There are two isoforms in this class, both of which have been shown to be important in regulating Rho-activity, and hence for cellular morphology and function.

Myosin X is a curious member. Apart from the structural demonstration of calf myosin X cDNA (GenBank

accession number U550421, very little is known about this class in terms of both biochemical and functional aspects, in spite of the recognition of intriguing domain structures in the tail: a cluster of pleckstrin homology

(PH) domains in addition to a coiled-coil domain, MyTH3 domain and talin-like domain. The PH domain is a protein module of about 100 amino acid residues, and is found in many signaling proteins and cytoskeletal components.

Molecular analysis of mouse myosin X, carried out by ourselves, has revealed a high degree of structural

homology between mouse and calf Xs, particularly in the PH domain (97%) and MyTH4 domain (96%) (Hanai et al., 1998). Northern blot analysis demonstrated that myosin X transcripts are widely expressed in both mouse

and human tissues (unpublished).

There are similarities in architecture among the tail regions of myosins X, VII and XV, the latter two of

1.5 C

Fig. 2 Mapping of My0 10 in mouse (upper panels) and human (lower panels) chromosomes by FISH. (a) Partial R-banded metaphase after FISH. The arrowheads indicate double-dot signals on mouse chr.15 and on the short-arm of human chr.5. (b) The same Q-banded metaphase as in a. (c) Schematic representations of mouse chr. 15 and human chr. 5, showing the sites of double-dot signals. A 1.5 kb cDNA fragment, which encompasses the third PH domain, MyTH4 domain and part of talin-like domain in the tail region of mouse myosin X, was obtained through screening of a BALBlc testis cDNA library (Clontech) and used as a probe for FISH. Sequence data indicate a high homology in tail region between mouse (GenBank, accession number AJZ19706) and calf (GenBank, accession number U55042) (93% at the amino acid level). Further details will appear elsewhere.


which are essential for the inner ear function, as described above. The My0 10 gene has been assigned to mouse chr.15C and to human chr.5p15.1-p14.3 by FISH (Fig. 2), comparable to the finding of Hasson et al. (1996). No mutant genes have been mapped to mouse chr.15C, but it i s of interest to note that the gene of craniometaphyseal dysplasia-Jackson type (CMDJ), which is syndromic, characterized by progressive deafness, optic atrophy, and mental and motor retardation as well as abnormal craniofacial features, has been mapped to a corresponding region (p15.2-p14.1) of human chr.5 (Nurnberg et al., 1997).

Concluding Remarks

Molecular genetic analyses of myosin-associated mouse mutant models and the precise examination of defective genes in myosin-associated human diseases have given valuable information about genotype- phenotype correlations. Further elucidation of the molecular basis of myosin-associated diseases should facilitate future prenatal diagnosis. To date, mutations in four different myosin genes have been identified as human disease-related, and those in five myosin genes as responsible for mouse mutants. Considering that several dozens of different myosin isoform genes exist in mammals, most of which have not yet been fully investigated, it is to be expected that more myosin genes will in future be identified as capable of causing human disease.

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Defective Myosin Genes in Mutant Mice and Human Diseases