A novel missense mutation in the FERM domain containing 7 (FRMD7) gene causing X-linked idiopathic congenital nystagmus in a Chinese family.
OBJECTIVE
Idiopathic congenital nystagmus (ICN) is a genetically heterogeneous disease. Thus far, the disease gene has been identified as the FERM domain containing 7 (FRMD7) gene. The purpose of this study was to elucidate the clinical and genetic characteristics of a four- generation Chinese family with ICN.


METHODS
The clinical data and the genomic DNA of a Chinese ICN family were collected following the provision of informed consent. All coding exons of the FRMD7 gene were amplified by PCR and then sequenced. Afﬁnity GST-p21 activated kinase 2 (PAK2) precipitation was used to investigate whether this novel FRMD7 mutant influenced Rac1 signaling activation in the human embryonic kidney 293 T cells (HEK 293T) cells transiently cotransfected with wild-type or mutant FRMD7 and Rac1.


RESULTS
A novel missense mutation (c.635T>C) was identified in all affected members. Obligate female carriers were heterozygous in these mutations and the affected males were homozygous, consistent with X-linked inheritance. This mutation is a substitution of proline for leucine. Function analysis showed that this novel mutant influences Rac1 signaling in human HEK 293T cells.


CONCLUSIONS
This study widens the mutation spectrum of the FRMD7 gene. This mutant was shown to activate GTPase Rac1 signaling in vitro; however, the quantity of activated Rac1 was obviously decreased compared with the wild type (p<0.05). Taken together, our data strongly support the hypothesis that the identified FRMD7 mutant influences GTPase Rac1 signaling, which regulates neurite development. This mutation may be related to the pathogenesis of X-linked ICN.
Department of Neurology, the Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, China.
Zhirong
Z
Liu
Shanying
S
Mao
Jiali
J
Pu
Yao
Y
Ding
Baorong
B
Zhang
Meiping
M
Ding
D000293:Adolescent; D000328:Adult; D000368:Aged; D044466:Asian People / Q000235:genetics*; D001483:Base Sequence; D002648:Child; D002681:China; D003598:Cytoskeletal Proteins / Q000235:genetics*; D004252:DNA Mutational Analysis; D005190:Family; D005260:Female; D040181:Genetic Diseases, X-Linked / Q000235:genetics*; D057809:HEK293 Cells; D006801:Humans; D007223:Infant; D008297:Male; D008565:Membrane Proteins / Q000235:genetics*; D008969:Molecular Sequence Data; D020125:Mutation, Missense / Q000235:genetics*; D020417:Nystagmus, Congenital / Q000235:genetics*; D010375:Pedigree; D017434:Protein Structure, Tertiary; D015398:Signal Transduction; D055815:Young Adult; D020830:rac1 GTP-Binding Protein / Q000378:metabolism
D003598:Cytoskeletal Proteins; C516168:FRMD7 protein, human; D008565:Membrane Proteins; D020830:rac1 GTP-Binding Protein