Whole-exome sequencing identifies a missense mutation in hnRNPA1 in a family with flail arm ALS.
OBJECTIVE
To identify the disease-causing gene of a family with upper limb predominant, slowly progressive amyotrophic lateral sclerosis (ALS), which was diagnosed as flail arm syndrome (FAS).


METHODS
After causation of 24 known ALS genes was excluded by targeted next-generation sequencing, whole-exome sequencing was applied in the FAS family. Cellular localization of mutant hnRNPA1 was examined in transfected HeLa cells. An additional 251 Chinese patients with ALS (including 7 sporadic FAS) underwent mutation screening of hnRNPA1.


RESULTS
We detected a novel missense mutation in hnRNPA1, c.862/1018C>T (p.P288S/P340S), which cosegregated with disease in the FAS family. The residue is highly conserved across species and exists in the encoded PY nuclear localization signal of hnRNPA1 protein. Mutant hnRNPA1 showed altered intracellular localization, resulting in formation of cytoplasmic inclusions that colocalized with stress granules in transfected cells. Further mutation screening of hnRNPA1 in additional patients with FAS and typical ALS detected 2 rare variants with unknown significance. These variants lie in the prion-like domain of hnRNPA1 long isoform, which was detected exclusively in the CNS.


CONCLUSIONS
Our results suggest that hnRNPA1 is the causative gene in the family with flail arm ALS. This further expanded the disease phenotype of hnRNPA1 mutations.
From the Department of Neurology and Laboratory of Clinical Genetics, Peking Union Medical College Hospital (Q.L., B.C., X.G.L., M.S.L., B.P., L.-y.C., X.Z.), and McKusick-Zhang Center for Genetic Medicine (S.S., R.R.W., F.L., X.N.G., C.X.L., X.Z.), Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing; and Neuroscience Center (Q.L., S.S., R.R.W., F.L., B.C., X.N.G., C.X.L., X.G.L., M.S.L., B.P., L.-y.C., X.Z.), Chinese Academy of Medical Sciences, Beijing, China.
Qing
Q
Liu
From the Department of Neurology and Laboratory of Clinical Genetics, Peking Union Medical College Hospital (Q.L., B.C., X.G.L., M.S.L., B.P., L.-y.C., X.Z.), and McKusick-Zhang Center for Genetic Medicine (S.S., R.R.W., F.L., X.N.G., C.X.L., X.Z.), Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing; and Neuroscience Center (Q.L., S.S., R.R.W., F.L., B.C., X.N.G., C.X.L., X.G.L., M.S.L., B.P., L.-y.C., X.Z.), Chinese Academy of Medical Sciences, Beijing, China.
Shi
S
Shu
From the Department of Neurology and Laboratory of Clinical Genetics, Peking Union Medical College Hospital (Q.L., B.C., X.G.L., M.S.L., B.P., L.-y.C., X.Z.), and McKusick-Zhang Center for Genetic Medicine (S.S., R.R.W., F.L., X.N.G., C.X.L., X.Z.), Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing; and Neuroscience Center (Q.L., S.S., R.R.W., F.L., B.C., X.N.G., C.X.L., X.G.L., M.S.L., B.P., L.-y.C., X.Z.), Chinese Academy of Medical Sciences, Beijing, China.
Rong Rong
RR
Wang
From the Department of Neurology and Laboratory of Clinical Genetics, Peking Union Medical College Hospital (Q.L., B.C., X.G.L., M.S.L., B.P., L.-y.C., X.Z.), and McKusick-Zhang Center for Genetic Medicine (S.S., R.R.W., F.L., X.N.G., C.X.L., X.Z.), Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing; and Neuroscience Center (Q.L., S.S., R.R.W., F.L., B.C., X.N.G., C.X.L., X.G.L., M.S.L., B.P., L.-y.C., X.Z.), Chinese Academy of Medical Sciences, Beijing, China.
Fang
F
Liu
From the Department of Neurology and Laboratory of Clinical Genetics, Peking Union Medical College Hospital (Q.L., B.C., X.G.L., M.S.L., B.P., L.-y.C., X.Z.), and McKusick-Zhang Center for Genetic Medicine (S.S., R.R.W., F.L., X.N.G., C.X.L., X.Z.), Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing; and Neuroscience Center (Q.L., S.S., R.R.W., F.L., B.C., X.N.G., C.X.L., X.G.L., M.S.L., B.P., L.-y.C., X.Z.), Chinese Academy of Medical Sciences, Beijing, China.
Bo
B
Cui
From the Department of Neurology and Laboratory of Clinical Genetics, Peking Union Medical College Hospital (Q.L., B.C., X.G.L., M.S.L., B.P., L.-y.C., X.Z.), and McKusick-Zhang Center for Genetic Medicine (S.S., R.R.W., F.L., X.N.G., C.X.L., X.Z.), Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing; and Neuroscience Center (Q.L., S.S., R.R.W., F.L., B.C., X.N.G., C.X.L., X.G.L., M.S.L., B.P., L.-y.C., X.Z.), Chinese Academy of Medical Sciences, Beijing, China.
Xia Nan
XN
Guo
From the Department of Neurology and Laboratory of Clinical Genetics, Peking Union Medical College Hospital (Q.L., B.C., X.G.L., M.S.L., B.P., L.-y.C., X.Z.), and McKusick-Zhang Center for Genetic Medicine (S.S., R.R.W., F.L., X.N.G., C.X.L., X.Z.), Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing; and Neuroscience Center (Q.L., S.S., R.R.W., F.L., B.C., X.N.G., C.X.L., X.G.L., M.S.L., B.P., L.-y.C., X.Z.), Chinese Academy of Medical Sciences, Beijing, China.
Chao Xia
CX
Lu
From the Department of Neurology and Laboratory of Clinical Genetics, Peking Union Medical College Hospital (Q.L., B.C., X.G.L., M.S.L., B.P., L.-y.C., X.Z.), and McKusick-Zhang Center for Genetic Medicine (S.S., R.R.W., F.L., X.N.G., C.X.L., X.Z.), Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing; and Neuroscience Center (Q.L., S.S., R.R.W., F.L., B.C., X.N.G., C.X.L., X.G.L., M.S.L., B.P., L.-y.C., X.Z.), Chinese Academy of Medical Sciences, Beijing, China.
Xiao Guang
XG
Li
From the Department of Neurology and Laboratory of Clinical Genetics, Peking Union Medical College Hospital (Q.L., B.C., X.G.L., M.S.L., B.P., L.-y.C., X.Z.), and McKusick-Zhang Center for Genetic Medicine (S.S., R.R.W., F.L., X.N.G., C.X.L., X.Z.), Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing; and Neuroscience Center (Q.L., S.S., R.R.W., F.L., B.C., X.N.G., C.X.L., X.G.L., M.S.L., B.P., L.-y.C., X.Z.), Chinese Academy of Medical Sciences, Beijing, China.
Ming Sheng
MS
Liu
From the Department of Neurology and Laboratory of Clinical Genetics, Peking Union Medical College Hospital (Q.L., B.C., X.G.L., M.S.L., B.P., L.-y.C., X.Z.), and McKusick-Zhang Center for Genetic Medicine (S.S., R.R.W., F.L., X.N.G., C.X.L., X.Z.), Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing; and Neuroscience Center (Q.L., S.S., R.R.W., F.L., B.C., X.N.G., C.X.L., X.G.L., M.S.L., B.P., L.-y.C., X.Z.), Chinese Academy of Medical Sciences, Beijing, China.
Bin
B
Peng
From the Department of Neurology and Laboratory of Clinical Genetics, Peking Union Medical College Hospital (Q.L., B.C., X.G.L., M.S.L., B.P., L.-y.C., X.Z.), and McKusick-Zhang Center for Genetic Medicine (S.S., R.R.W., F.L., X.N.G., C.X.L., X.Z.), Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing; and Neuroscience Center (Q.L., S.S., R.R.W., F.L., B.C., X.N.G., C.X.L., X.G.L., M.S.L., B.P., L.-y.C., X.Z.), Chinese Academy of Medical Sciences, Beijing, China.
Li-Ying
LY
Cui
From the Department of Neurology and Laboratory of Clinical Genetics, Peking Union Medical College Hospital (Q.L., B.C., X.G.L., M.S.L., B.P., L.-y.C., X.Z.), and McKusick-Zhang Center for Genetic Medicine (S.S., R.R.W., F.L., X.N.G., C.X.L., X.Z.), Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing; and Neuroscience Center (Q.L., S.S., R.R.W., F.L., B.C., X.N.G., C.X.L., X.G.L., M.S.L., B.P., L.-y.C., X.Z.), Chinese Academy of Medical Sciences, Beijing, China. xuezhang@pumc.edu.cn.
Xue
X
Zhang
D000328:Adult; D000368:Aged; D000690:Amyotrophic Lateral Sclerosis / Q000235:genetics* / Q000473:pathology*; D001132:Arm / Q000503:physiopathology*; D059472:Exome / Q000235:genetics; D005192:Family Health; D005260:Female; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D000076245:Heterogeneous Nuclear Ribonucleoprotein A1; D034481:Heterogeneous-Nuclear Ribonucleoprotein Group A-B / Q000235:genetics*; D006801:Humans; D051666:Kv1.5 Potassium Channel / Q000235:genetics; D008297:Male; D020125:Mutation, Missense / Q000235:genetics*; D012720:Severity of Illness Index
D000076245:Heterogeneous Nuclear Ribonucleoprotein A1; D034481:Heterogeneous-Nuclear Ribonucleoprotein Group A-B; D051666:Kv1.5 Potassium Channel; C000619656:hnRNPA1 protein, human