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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doaj-7993c255cac4414780d8346e71c837282021-09-16T05:18:30ZengFrontiers Media S.A.Frontiers in Genetics1664-80212021-09-011210.3389/fgene.2021.715599715599Case Report: A Novel Missense Variant in the SIPA1L3 Gene Associated With Cataracts in a Chinese FamilyDuo Yang0Haiyan Zhou1Jiwu Lin2Shuangxi Zhao3Hao Zhou4Zhaochu Yin5Bin Ni6Yong Chen7Wanqin Xie8Department of Ophthalmology, The Jili Hospital of Liuyang and the Eye Hospital of Liuyang, Changsha, ChinaNational Health Committee Key Laboratory of Birth Defects for Research and Prevention, Hunan Provincial Maternal and Child Health Care Hospital, Changsha, ChinaNational Health Committee Key Laboratory of Birth Defects for Research and Prevention, Hunan Provincial Maternal and Child Health Care Hospital, Changsha, ChinaDepartment of Ophthalmology, The Jili Hospital of Liuyang and the Eye Hospital of Liuyang, Changsha, ChinaState Key Laboratory of Medicinal Chemical Biology, Tianjin Key Laboratory of Protein Science, College of Life Sciences, Nankai University, Tianjin, ChinaNational Health Committee Key Laboratory of Birth Defects for Research and Prevention, Hunan Provincial Maternal and Child Health Care Hospital, Changsha, ChinaNational Health Committee Key Laboratory of Birth Defects for Research and Prevention, Hunan Provincial Maternal and Child Health Care Hospital, Changsha, ChinaNational Health Committee Key Laboratory of Birth Defects for Research and Prevention, Hunan Provincial Maternal and Child Health Care Hospital, Changsha, ChinaNational Health Committee Key Laboratory of Birth Defects for Research and Prevention, Hunan Provincial Maternal and Child Health Care Hospital, Changsha, ChinaThe 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.https://www.frontiersin.org/articles/10.3389/fgene.2021.715599/fullRap GTPaseGTPase-activating proteinSIPA1L3RapGAPcataract |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Duo Yang Haiyan Zhou Jiwu Lin Shuangxi Zhao Hao Zhou Zhaochu Yin Bin Ni Yong Chen Wanqin Xie |
spellingShingle |
Duo Yang Haiyan Zhou Jiwu Lin Shuangxi Zhao Hao Zhou Zhaochu Yin Bin Ni Yong Chen Wanqin Xie Case Report: A Novel Missense Variant in the SIPA1L3 Gene Associated With Cataracts in a Chinese Family Frontiers in Genetics Rap GTPase GTPase-activating protein SIPA1L3 RapGAP cataract |
author_facet |
Duo Yang Haiyan Zhou Jiwu Lin Shuangxi Zhao Hao Zhou Zhaochu Yin Bin Ni Yong Chen Wanqin Xie |
author_sort |
Duo Yang |
title |
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_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_sort |
case report: a novel missense variant in the sipa1l3 gene associated with cataracts in a chinese family |
publisher |
Frontiers Media S.A. |
series |
Frontiers in Genetics |
issn |
1664-8021 |
publishDate |
2021-09-01 |
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. |
topic |
Rap GTPase GTPase-activating protein SIPA1L3 RapGAP cataract |
url |
https://www.frontiersin.org/articles/10.3389/fgene.2021.715599/full |
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