A Novel Missense Mutation in the FERM Domain Containing 7 (FRMD7) Gene Causing X-linked Idiopathic Congenital Nystagmus in a Chinese Family

Overview

Journal Mol Vis

Specialties Cell Biology
Molecular Biology
Ophthalmology

Date 2013 Aug 16

PMID 23946638

Citations 10

Authors

Zhirong Liu

Shanying Mao

Jiali Pu

Yao Ding

Baorong Zhang

Meiping Ding

Affiliations

Soon will be listed here.

Abstract

Purpose: 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.

Citing Articles

Surgical outcomes of a congenital nystagmus family with a missense mutation in the FRMD7 gene.

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X-linked FRMD7 gene mutation in idiopathic congenital nystagmus and its role in eye movement: A case report and literature review.

Liu F, Wang M, Liao M, Liu L, Jiang X Front Ophthalmol (Lausanne). 2024; 2:1080869.

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Truncated FRMD7 proteins in congenital Nystagmus: novel frameshift mutations and proteasomal pathway implications.

Su Y, Zhang J, Gao J, Ding G, Jiang H, Liu Y BMC Med Genomics. 2024; 17(1):36.

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Gene Alterations in a Pakistani Family Associated with Congenital Idiopathic Nystagmus.

Arshad M, Shabbir M, Asif S, Shahzad M, Leydier L, Rai S Genes (Basel). 2023; 14(2).

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De novo variants in FRMD5 are associated with developmental delay, intellectual disability, ataxia, and abnormalities of eye movement.

Lu S, Ma M, Mao X, Bacino C, Jankovic J, Sutton V Am J Hum Genet. 2022; 109(10):1932-1943.

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References

Pu J, Li Y, Liu Z, Yan Y, Tian J, Chen S . Expression and localization of FRMD7 in human fetal brain, and a role for F-actin. Mol Vis. 2011; 17:591-7. PMC: 3049738. View

Betts-Henderson J, Bartesaghi S, Crosier M, Lindsay S, Chen H, Salomoni P . The nystagmus-associated FRMD7 gene regulates neuronal outgrowth and development. Hum Mol Genet. 2009; 19(2):342-51. DOI: 10.1093/hmg/ddp500. View

Tahirovic S, Hellal F, Neukirchen D, Hindges R, Garvalov B, Flynn K . Rac1 regulates neuronal polarization through the WAVE complex. J Neurosci. 2010; 30(20):6930-43. PMC: 6632643. DOI: 10.1523/JNEUROSCI.5395-09.2010. View

Yan N, Liao X, Cai S, Lan C, Wang Y, Zhou X . A novel nonsense mutation of the GPR143 gene identified in a Chinese pedigree with ocular albinism. PLoS One. 2012; 7(8):e43177. PMC: 3423421. DOI: 10.1371/journal.pone.0043177. View

Chishti A, Kim A, Marfatia S, Lutchman M, Hanspal M, Jindal H . The FERM domain: a unique module involved in the linkage of cytoplasmic proteins to the membrane. Trends Biochem Sci. 1998; 23(8):281-2. DOI: 10.1016/s0968-0004(98)01237-7. View

Watkins R, Patil R, Goult B, Thomas M, Gottlob I, Shackleton S . A novel interaction between FRMD7 and CASK: evidence for a causal role in idiopathic infantile nystagmus. Hum Mol Genet. 2013; 22(10):2105-18. PMC: 3633374. DOI: 10.1093/hmg/ddt060. View

Schorderet D, Tiab L, Gaillard M, Lorenz B, Klainguti G, Kerrison J . Novel mutations in FRMD7 in X-linked congenital nystagmus. Mutation in brief #963. Online. Hum Mutat. 2007; 28(5):525. DOI: 10.1002/humu.9492. View

Zhang B, Liu Z, Zhao G, Xie X, Yin X, Hu Z . Novel mutations of the FRMD7 gene in X-linked congenital motor nystagmus. Mol Vis. 2007; 13:1674-9. View

Akasaki T, Koga H, Sumimoto H . Phosphoinositide 3-kinase-dependent and -independent activation of the small GTPase Rac2 in human neutrophils. J Biol Chem. 1999; 274(25):18055-9. DOI: 10.1074/jbc.274.25.18055. View

10.

Baines A . A FERM-adjacent (FA) region defines a subset of the 4.1 superfamily and is a potential regulator of FERM domain function. BMC Genomics. 2006; 7:85. PMC: 1459144. DOI: 10.1186/1471-2164-7-85. View

11.

Kerrison J, Vagefi M, Barmada M, Maumenee I . Congenital motor nystagmus linked to Xq26-q27. Am J Hum Genet. 1999; 64(2):600-7. PMC: 1377771. DOI: 10.1086/302244. View

12.

Nikolic M . The role of Rho GTPases and associated kinases in regulating neurite outgrowth. Int J Biochem Cell Biol. 2002; 34(7):731-45. DOI: 10.1016/s1357-2725(01)00167-4. View

13.

Zhou P, Wang Z, Zhang J, Hu L, Kong X . Identification of a novel GPR143 deletion in a Chinese family with X-linked congenital nystagmus. Mol Vis. 2008; 14:1015-9. PMC: 2408774. View

14.

Fingert J, Roos B, Eyestone M, Pham J, Mellot M, Stone E . Novel intragenic FRMD7 deletion in a pedigree with congenital X-linked nystagmus. Ophthalmic Genet. 2010; 31(2):77-80. DOI: 10.3109/13816810903584989. View

15.

Watkins R, Thomas M, Talbot C, Gottlob I, Shackleton S . The Role of FRMD7 in Idiopathic Infantile Nystagmus. J Ophthalmol. 2011; 2012:460956. PMC: 3163398. DOI: 10.1155/2012/460956. View

16.

Li N, Wang L, Cui L, Zhang L, Dai S, Li H . Five novel mutations of the FRMD7 gene in Chinese families with X-linked infantile nystagmus. Mol Vis. 2008; 14:733-8. PMC: 2324116. View

17.

Liu J, Ren X, Yang X, Guo T, Yao Q, Li L . Identification of a novel GPR143 mutation in a large Chinese family with congenital nystagmus as the most prominent and consistent manifestation. J Hum Genet. 2007; 52(6):565-570. DOI: 10.1007/s10038-007-0152-3. View

18.

Kubo T, Yamashita T, Yamaguchi A, Sumimoto H, Hosokawa K, Tohyama M . A novel FERM domain including guanine nucleotide exchange factor is involved in Rac signaling and regulates neurite remodeling. J Neurosci. 2002; 22(19):8504-13. PMC: 6757789. View

19.

Zhuang B, Su Y, Sockanathan S . FARP1 promotes the dendritic growth of spinal motor neuron subtypes through transmembrane Semaphorin6A and PlexinA4 signaling. Neuron. 2009; 61(3):359-72. PMC: 2654783. DOI: 10.1016/j.neuron.2008.12.022. View

20.

Tarpey P, Thomas S, Sarvananthan N, Mallya U, Lisgo S, Talbot C . Mutations in FRMD7, a newly identified member of the FERM family, cause X-linked idiopathic congenital nystagmus. Nat Genet. 2006; 38(11):1242-4. PMC: 2592600. DOI: 10.1038/ng1893. View