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Case Report: A Novel Missense Variant in the SIPA1L3 Gene Associated With Cataracts in a Chinese Family

The signal-induced proliferation-associated 1-like 3 (SIPA1L3) gene that encodes a putative Rap GTPase-activating protein (RapGAP) has been associated with congenital cataract and eye development abnormalities. However, our current understanding of the mutation spectrum of SIPA1L3 associated with ey...

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Autores principales: Yang, Duo, Zhou, Haiyan, Lin, Jiwu, Zhao, Shuangxi, Zhou, Hao, Yin, Zhaochu, Ni, Bin, Chen, Yong, Xie, Wanqin
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8481882/
https://www.ncbi.nlm.nih.gov/pubmed/34603379
http://dx.doi.org/10.3389/fgene.2021.715599
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author Yang, Duo
Zhou, Haiyan
Lin, Jiwu
Zhao, Shuangxi
Zhou, Hao
Yin, Zhaochu
Ni, Bin
Chen, Yong
Xie, Wanqin
author_facet Yang, Duo
Zhou, Haiyan
Lin, Jiwu
Zhao, Shuangxi
Zhou, Hao
Yin, Zhaochu
Ni, Bin
Chen, Yong
Xie, Wanqin
author_sort Yang, Duo
collection PubMed
description The signal-induced proliferation-associated 1-like 3 (SIPA1L3) gene that encodes a putative Rap GTPase-activating protein (RapGAP) has been associated with congenital cataract and eye development abnormalities. However, our current understanding of the mutation spectrum of SIPA1L3 associated with eye defects is limited. By using whole-exome sequencing plus Sanger sequencing validation, we identified a novel heterozygous c.1871A > G (p.Lys624Arg) variation within the predicted RapGAP domain of SIPA1L3 in the proband with isolated juvenile-onset cataracts from a three-generation Chinese family. In this family, the proband's father and grandmother were also heterozygous for the c.1871A > G variation and affected by cataracts varying in morphology, severity, and age of onset. Sequence alignment shows that the Lys 624 residue of SIPA1L3 is conserved across the species. Based on the resolved structure of Rap1–Rap1GAP complex, homology modeling implies that the Lys 624 residue is structurally homologous to the Lys 194 of Rap1GAP, a highly conserved lysine residue that is involved in the interface between Rap1 and Rap1GAP and critical for the affinity to Rap·GTP. We reasoned that arginine substitution of lysine 624 might have an impact on the SIPA1L3-Rap·GTP interaction, thereby affecting the regulatory function of SIPA1L3 on Rap signaling. Collectively, our finding expands the mutation spectrum of SIPA1L3 and provides new clues to the molecular mechanisms of SIPA1L3-related cataracts. Further investigations are warranted to validate the functional alteration of the p.Lys624Arg variant of SIPA1L3.
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spelling pubmed-84818822021-10-01 Case Report: A Novel Missense Variant in the SIPA1L3 Gene Associated With Cataracts in a Chinese Family Yang, Duo Zhou, Haiyan Lin, Jiwu Zhao, Shuangxi Zhou, Hao Yin, Zhaochu Ni, Bin Chen, Yong Xie, Wanqin Front Genet Genetics The signal-induced proliferation-associated 1-like 3 (SIPA1L3) gene that encodes a putative Rap GTPase-activating protein (RapGAP) has been associated with congenital cataract and eye development abnormalities. However, our current understanding of the mutation spectrum of SIPA1L3 associated with eye defects is limited. By using whole-exome sequencing plus Sanger sequencing validation, we identified a novel heterozygous c.1871A > G (p.Lys624Arg) variation within the predicted RapGAP domain of SIPA1L3 in the proband with isolated juvenile-onset cataracts from a three-generation Chinese family. In this family, the proband's father and grandmother were also heterozygous for the c.1871A > G variation and affected by cataracts varying in morphology, severity, and age of onset. Sequence alignment shows that the Lys 624 residue of SIPA1L3 is conserved across the species. Based on the resolved structure of Rap1–Rap1GAP complex, homology modeling implies that the Lys 624 residue is structurally homologous to the Lys 194 of Rap1GAP, a highly conserved lysine residue that is involved in the interface between Rap1 and Rap1GAP and critical for the affinity to Rap·GTP. We reasoned that arginine substitution of lysine 624 might have an impact on the SIPA1L3-Rap·GTP interaction, thereby affecting the regulatory function of SIPA1L3 on Rap signaling. Collectively, our finding expands the mutation spectrum of SIPA1L3 and provides new clues to the molecular mechanisms of SIPA1L3-related cataracts. Further investigations are warranted to validate the functional alteration of the p.Lys624Arg variant of SIPA1L3. Frontiers Media S.A. 2021-09-16 /pmc/articles/PMC8481882/ /pubmed/34603379 http://dx.doi.org/10.3389/fgene.2021.715599 Text en Copyright © 2021 Yang, Zhou, Lin, Zhao, Zhou, Yin, Ni, Chen and Xie. https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Genetics
Yang, Duo
Zhou, Haiyan
Lin, Jiwu
Zhao, Shuangxi
Zhou, Hao
Yin, Zhaochu
Ni, Bin
Chen, Yong
Xie, Wanqin
Case Report: A Novel Missense Variant in the SIPA1L3 Gene Associated With Cataracts in a Chinese Family
title Case Report: A Novel Missense Variant in the SIPA1L3 Gene Associated With Cataracts in a Chinese Family
title_full Case Report: A Novel Missense Variant in the SIPA1L3 Gene Associated With Cataracts in a Chinese Family
title_fullStr Case Report: A Novel Missense Variant in the SIPA1L3 Gene Associated With Cataracts in a Chinese Family
title_full_unstemmed Case Report: A Novel Missense Variant in the SIPA1L3 Gene Associated With Cataracts in a Chinese Family
title_short Case Report: A Novel Missense Variant in the SIPA1L3 Gene Associated With Cataracts in a Chinese Family
title_sort case report: a novel missense variant in the sipa1l3 gene associated with cataracts in a chinese family
topic Genetics
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8481882/
https://www.ncbi.nlm.nih.gov/pubmed/34603379
http://dx.doi.org/10.3389/fgene.2021.715599
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