1. Academic Validation
  2. Truncated FRMD7 proteins in congenital Nystagmus: novel frameshift mutations and proteasomal pathway implications

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

  • BMC Med Genomics. 2024 Jan 26;17(1):36. doi: 10.1186/s12920-024-01817-7.
Yuqing Su # 1 2 Juntao Zhang # 3 Jiahui Gao 1 Guoqing Ding 1 Heng Jiang 1 Yang Liu 3 Yulei Li 4 5 Guohua Yang 6 7
Affiliations

Affiliations

  • 1 Department of Medical Genetics, School of Basic Medical Science, Wuhan University, Wuhan, China.
  • 2 The First Clinical College of Wuhan University, Wuhan, China.
  • 3 Xiangyang Central Hospital, Affiliated Hospital of Hubei University of Arts and Science, Xiangyang, 441021, China.
  • 4 Xiangyang Central Hospital, Affiliated Hospital of Hubei University of Arts and Science, Xiangyang, 441021, China. liyulei@126.com.
  • 5 School of Basic Medicine, Hubei University of Arts and Science, Xiangyang, 441053, China. liyulei@126.com.
  • 6 Department of Medical Genetics, School of Basic Medical Science, Wuhan University, Wuhan, China. ghyang@whu.edu.cn.
  • 7 Hubei Provincial Key Laboratory of Developmentally Originated Disease, Wuhan, 430071, China. ghyang@whu.edu.cn.
  • # Contributed equally.
Abstract

Idiopathic congenital nystagmus (ICN) manifests as involuntary and periodic eye movements. To identify the genetic defect associated with X-linked ICN, Whole Exome Sequencing (WES) was conducted in two affected families. We identified two frameshift mutations in FRMD7, c.1492dupT/p.(Y498Lfs*15) and c.1616delG/p.(R539Kfs*2). Plasmids harboring the mutated genes and qPCR analysis revealed mRNA stability, evading degradation via the NMD pathway, and corroborated truncated protein production via Western-blot analysis. Notably, both truncated proteins were degraded through the proteasomal (ubiquitination) pathway, suggesting potential therapeutic avenues targeting this pathway for similar mutations. Moreover, we conducted a comprehensive analysis, summarizing 140 mutations within the FRMD7 gene. Our findings highlight the FERM and FA structural domains as mutation-prone regions. Interestingly, exons 9 and 12 are the most mutated regions, but 90% (28/31) mutations in exon 9 are missense while 84% (21/25) mutations in exon 12 are frameshift. A predominant occurrence of shift code mutations was observed in exons 11 and 12, possibly associated with the localization of premature termination codons (PTCs), leading to the generation of deleterious truncated proteins. Additionally, our conjecture suggests that the loss of FRMD7 protein function might not solely drive pathology; rather, the emergence of aberrant protein function could be pivotal in nystagmus etiology. We propose a dependence of FRMD7 protein normal function primarily on its anterior domain. Future investigations are warranted to validate this hypothesis.

Keywords

Congenital nystagmus; FRMD7; Function validation, X-linked nystagmus; Novel mutation.

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