1

GFAP variants associated with Alexander disease

(mostly published, plus a few unpublished – please note that the level of proof for disease causation varies)

(updated May 28, 2018)

see bottom to view Alexander Disease patients without mutations as well as links to references giving innocuous polymorphisms

Mutation Reported as

patient # Reference

K63Q 1 (Li et al., 2005)

R66G Flones 2015

R66Q (Prust et al., 2011)

R66Q (Hida et al., 2012)

R66Q Luiz Pedroso et al. 2014

E69K (Busch et al., 2006 abstract) (Davison et al., 2011)

E69K Kondo 2016

E69K Brackmann (in press)

R70Q 12 (Caroli et al., 2007) and #1 in Jany

et al. 2015

R70Q 11 Graff-Radford et al. 2014

R70W (Salvi et. al., 2005)

R70W (Sreedharan, et al, 2007)

R70W 9 (Yoshida et al., 2011)

R70W D Yoshida 2015

E72K (Prust et al., 2011)

M73K (Caroli et al., 2007)

M73R 8 (Gorospe et al., 2002)

M73T 2 (Li et al., 2005)

M73T (Vazquez 2008)

2

M73T, V87F Liang 2017

M74T (Ohnari et al, 2007)

M74T 11 (Yoshida et al, 2010)

L76F 1 (Rodriguez et al., 2001)

L76F 3 (Li et al., 2005)

L76F 9 Zang et al. 2013

L76H or Q? complicated genetics Tavasoli 2017

L76V 4 (Li et al., 2005)

N77K 15 Zang et al. 2013

N77S 5 (Li et al., 2005)

N77S (Caroli et al., 2007)

N77S 2-3 Jany et al. 2015

N77S, S152L 4 Jany et al. 2015

N77Y 2 (Rodriguez et al., 2001)

D78E familial, adult onset (Stumpf et al., 2003)

D78N Wada et al. 2013

D78Y 1 Tonduti 2016

R79C 1 & 12 (Brenner et al., 2001)

R79C . (Probst et al. 2003)

R79C 2 (Gorospe et al., 2002)

R79C 1, 2 (Shiroma et al., 2003)

R79C 6-8 (Li et al., 2005) and #5 in Jany et al. 2015

R79C 3-5 (Caroli et al., 2007)

R79C Matarese et al. 2008 and #6 in Jany et al. 2015

R79C (Mignot 2009)

R79C (Biancheri et al., 2012)

R79C 14, 16, 19 Zang et al. 2013

R79C 7-8 Jany et al. 2015

R79G 1 (Gorospe et al., 2002)

3

R79G 9 Jany 2015

R79H 2 & 13 (Brenner et al., 2001)

R79H 3 & 4 (Gorospe et al., 2002)

R79H 2-3 (twins) (Meins et al., 2002)

R79H 3, 4, 5, & 6 (Rodriguez et al., 2001)

R79H (Asahina 2006)

R79H 10 (Yoshida et al., 2010)

R79H 13,17 (Zang et al. 2013)

R79H 8 Yoshida et al., 2013

R79H 2 Ashrafi et al., 2013

R79H 10-13 Jany 2015

R79H & E223Q (Dotti et al., 2009)

R79L 4 (Shiroma et al., 2003) (Imamura et al., 2002)

R79L 8 Zang et al. 2013

R79L 14 Jany 2015

R79P (Caroli et al., 2007)

R79S (Prust et al., 2011)

F80S

da Silva Pereira et al. 2013 (parents not tested

Y83H 1 (Wu et al. 2008)

I84F 20 Wang 2016

K86E 3 (Barreau et al., 2011)

K86V87delinsEF 2 (van der Knaap et. al., 2006)

V87G familial, adult-onset (Okamoto et al., 2002)

V87G 4-5 (Yoshida et al., 2010)

V87I Restrepo et al., 2011

V87I 6 Graff-Radford et al. 2014

V87L (Suzuki et al., 2012)

4

R88C 9 & 10 (Gorospe et al., 2002) and #15 in Jany et al. 2015

R88C 7 & 8 (Rodriguez et al., 2001)

R88C 9 (Li et al., 2005)

R88C (Nobuhara et al. 2004)

R88C 1 (Kyllerman et al. 2005)

R88C 3,4 (mother-son pair), 7 (van der Knaap et. al., 2006) and #19-20 in Jany et al. 2015

R88C (Caroli et al., 2007)

R88C 2-3 (Wu et al. 2008)

R88C 1,2,3,11 Zang et al. 2013

R88C 16-18 Jany 2015

R88C 2,3 (mother-son pair) Tonduti 2016

R88S 9 (Rodriguez et al., 2001)

R88S 10 Zang et al. 2013

L90P (Suzuki et al. 2004)

Q93P 2 (Kyllerman et al. 2005)

L97P 4 (Meins et al., 2002)

L97P 10 (Li et al., 2005)

L101P (Kaneko et al., 2009)

N102K 11 Yoshida 2017

R105W 21

pathogenicity uncertain Jany et al. 2015

T110S pathogenicity uncertain (unpublished)

L123P 22 Jany 2015

L123P 19 Yoshida 2017

RL124-125insQLR Schmidt et al. 2013

RL124-125insE 18 Yoshida 2017

RL126-127ins 1 (van der Knaap et. al., 2006)

5

RL126-127dup 15 Yoshida 2017

D128N 10 (Pareyson 2008); (Farina 2008)

D128N Chang et al 2015

D128N Lee 2017

R201del Varanda 2015

E205K 5, 8 (Pareyson 2008); (Farina 2008)

E207K 11 (Li et al., 2005)

E207Q 12 (Li et al., 2005); #7 in van der Knaap 2005; #23 in Jany et al. 2015

E207V Gass 2017

E210K 13 (Li et al., 2005)

E210K 3 (Kyllerman et al. 2005)

E210K 6 (van der Knaap et. al., 2006)

E210K B Yoshida 2015

E223Q familial, adult-onset (Brockmann et al., 2003)

L231H parent of below Delnooz 2008; #24 in Jany 2015

L231H 25 Jany 2015

L235P 14-15 twins (Li et al., 2005)

L235P 16 (Li et al., 2005)

K236T (Prust et al., 2011)

R239C 3, 4, 5, & 6 (Brenner et al., 2001)

R239C 5 (Gorospe et al., 2002)

R239C 1 (Meins et al., 2002)

R239C 10, 11, 12, & 13 (Rodriguez et al., 2001)

R239C . (Shiroma et al., 2001)

R239C . (Shiihara et al., 2002)

R239C 3 (Shiroma et al., 2003)

R239C 17-22 (Li et al., 2005)

6

R239C 2 (Barreau et al., 2011)

R239C 4-5 Zang et al. 2013

R239C 26-29 Jany 2015

R239G (Osorio et al., 2012)

R239G 7 Graff-Radford et al. 2014

R239H 7 (Brenner et al., 2001)

R239H 14 (Rodriguez et al., 2001)

R239H . (Trollmann et al., 2003)

R239H 23-27 (Li et al., 2005)

R239H (Caroli et al., 2007)

R239H 1 Ashrafi et al., 2013

R239H 18,20,21 Zang et al. 2013

R239H Goyal et al 2014

R239H 30-31 Jany 2015

R239L (Lee et al., 2006)

R239L (Shiihara et al., 2011)

R239P 5 (Meins et al., 2002)

R239P #28 in (Li et al., 2005); #1 in van der Knaap 2005; #32 in Jany 2015

R239P (Caroli et al., 2007)

R239P 33 Jany 2015

Y242D 6 (Gorospe et al., 2002)

Y242N mother-son pair Ogura, 2016

E243dup Yasuda 2017

A244V . (Aoki et al., 2001)

A244V 29 (Li et al., 2005)

A244V 9 Yoshida 2017

A244V Kawai 2017

S247P family A (Messing et al, 2012); #34 in Jany 2015

7

A253G 30 (Li et al., 2005)

Y257C (Howard et al. 2008)

R258C 8 (Yoshida et al., 2010)

R258C Spritzer et al., 2013

R258C Jost 2017

R258H C Yoshida 2015

R258P 8 (Brenner et al., 2001)

R258P 35 Jany 2015

L264P (Ayaki et al., 2010)

L264P 9 Graff-Radford et al. 2014

A267P (Hinttala et al., 2007)

A267P Lee et al, 2014

A268D 9 Yoshida et al., 2013

A268D 1 Yoshida 2017

R270L Ito et al., 2011 – abstract

R270P de Paiva 2016

R270_A272del 36 Jany 2015

R276C 2 Ahmad 2015

R276L familial, adult-onset (Namekawa et al. 2002)

R276L (Namekawa et al., 2010)

R276L (Namekawa et al., 2012)

K279E 31 (Li et al., 2005)

D284Y 1 Ahmad 2015

Q290E 1 (Barreau et al., 2011); #37 in Jany 2015

G301D 10 Yoshida 2017

E312* Nam et al. 2014

E312K Bonthius 2016

L331P reduced penetrance? (Shiihara et al. 2004)

E332del (Jefferson et al. 2010)

8

R330G, E332K E332K likely the pathogenic one

(Balbi et al. 2008)

L338P unpublished

L346S 2 Garcia-Reitboeck 2015

349Hlins 32 (Li et al., 2005)

D351H (Tschampa et al., 2011)

L352P severe, 33 (same

patient) (Bassuk et al. 2003), (Li et al., 2005)

L357P (Niinikoski et al., 2009)

L357P 12 (Yoshida et al., 2011)

L357P 17 Yoshida 2017

A358V (Dinopoulos et al. 2006)

L359P (Romano et al 2007) (also probably same patient listed as #11 in Caroli et al., 2007)

L359V 34 (Li et al., 2005)

L359V (Ramesh et al., 2013)

D360N Scola et al, 2014

D360V (Ishigaki et al. 2006)

E362D . (Sawaishi et al., 2002)

E362G 55 Yoshida et al., 2013

E362Q 38 Jany 2015

I363V Nam 2017

A364P 35 (Li et al., 2005)

A364V (Hartmann et al., 2007)

Y366C (Hartmann et al., 2007)

Y366H 36 (Li et al., 2005)

E371G (Kawai et. al., 2006)

E371Q (Prust et al., 2011)

E371Q 39 Jany 2015

E371V (Prust et al., 2011)

9

E373A 12-13

mother-daughter pair Graff-Radford et al. 2014

E373A 40 Jany 2015

E373D 7 Zang et al. 2013

E373K 7 (Gorospe et al., 2002)

E373K 37-38 (Li et al., 2005)

E373K (Matej et al 2008)

E373Q 39 (Li et al., 2005)

E374G 40 (Li et al., 2005); #41 in Jany 2015

E374Q Zang et al. 2013

R376G (Prust et al., 2011)

R376W (Hirayama et al. 2008)

R376W Prust et al., 2011

R376W Zafeiriou et al. 2013

R376W Boczek 2017

T383I (Schmidt et al., 2011)

S385C 3 &10

father-son pair Graff-Radford et al. 2014

S385C 1 Garcia-Reitboeck 2015

S385F (Torisu et al., 2013)

S385F 6 Zang et al. 2013

N386I (Caceres-Marzal et al., 2006)

N386S Sugiyama et al. 2015

N386S A Yoshida 2015

N386S 6, 8 Yoshida 2017

N386S McAuley 2017

N386S Lichtenstein 2017

S393I (Salmaggi et al., 2007)

10

S393R Iwasaki et al 2015

S398F (Sueda et al., 2009)

S398F Di Giovanni 2016

S398F 42 Jany 2015

S398Y 9 (Pareyson 2008); (Farina 2008); #43 in Jany 2015

M415I mother-daughter (de Souza Rezende et al., 2012); #44-45 in Jany 2015

M415I adult, familial

(reported incorrectly as 451)

Elmali 2016

R416W 9 & 10 (Brenner et al., 2001)

R416W 11 & 12 (Gorospe et al., 2002)

R416W adult-onset (Kinoshita et al. 2003)

R416W adult-onset (Thyagarajan et al. 2004)

R416W 41 (Li et al., 2005)

R416W 5 (van der Knaap et. al., 2006)

R416W #10 in (Caroli et al., 2007); #3 in Pareyson, 2008 and Farina 2008; # 47 in Jany 2015

R416W Nishri et al. 2014

R416W 46, 48-49 Jany 2015

R416W Liu 2016

R416W 2, 16 Yoshida 2017

D417Mfs*15 deletion, frame-shift (Murakami et al. 2008)

D417Mfs*15 deletion, frame-shift (Flint et al., 2012)

D417A family B (Messing et al., 2012)

Q426L family C (Messing et al., 2012); #50 in Jany 2015

V431Dfs*14 mosaic (Flint et al., 2012)

IVS-3C>G aberrant splicing, deletes exon 4,

encoding E207-K260 (Flint et al., 2012)

11

IVS2-24_c812delins

(insertion is of 20bp)

5 pathogenicity not

proven, but predicted to cause aberrant splicing with deletion of exon 5, encoding F261-T302

Graff-Radford et al. 2014

del F261-T302 Deletion of exon 5 Green 2018

12

Alexander disease patients in whom no GFAP mutations were found

Mutation Reported as patient # In reference

None 11 (Brenner et al., 2001)

None 15 (Rodriguez et al., 2001)

None 13 (Gorospe et al., 2002)

None 43-44 (Li et al., 2005)

None (Huttner et al., 2007)

Polymorphisms - see Li et al, 2005 and Li et al, 2006 for earlier summary, though more current listings are included in online databases such as the following:

Human Intermediate Filament Database

Exome Variants Server

Exac Browser