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SOX10 Mutation Screening for 117 Patients with Kallmann Syndrome
INTRODUCTION: Kallmann syndrome (KS) is a genetically heterogeneous condition characterized by hypogonadotropic hypogonadism (HH) and olfactory dysfunction. Although SOX10, a causative gene for Waardenburg syndrome (WS) and peripheral demyelinating neuropathy, central demyelination, WS, and Hirschsp...
Autores principales: | , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
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Oxford University Press
2021
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8170842/ https://www.ncbi.nlm.nih.gov/pubmed/34095692 http://dx.doi.org/10.1210/jendso/bvab056 |
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author | Shima, Hirohito Tokuhiro, Etsuro Okamoto, Shingo Nagamori, Mariko Ogata, Tsutomu Narumi, Satoshi Nakamura, Akie Izumi, Yoko Jinno, Tomoko Suzuki, Erina Fukami, Maki |
author_facet | Shima, Hirohito Tokuhiro, Etsuro Okamoto, Shingo Nagamori, Mariko Ogata, Tsutomu Narumi, Satoshi Nakamura, Akie Izumi, Yoko Jinno, Tomoko Suzuki, Erina Fukami, Maki |
author_sort | Shima, Hirohito |
collection | PubMed |
description | INTRODUCTION: Kallmann syndrome (KS) is a genetically heterogeneous condition characterized by hypogonadotropic hypogonadism (HH) and olfactory dysfunction. Although SOX10, a causative gene for Waardenburg syndrome (WS) and peripheral demyelinating neuropathy, central demyelination, WS, and Hirschsprung disease (PCWH) has previously been implicated in KS, the clinical significance of SOX10 variants as the cause of KS remains uncertain. PATIENTS AND METHODS: A total of 117 patients with KS underwent mutation screening of SOX10 and 14 other causative genes for KS/HH. Rare SOX10 variants were subjected to in silico and in vitro analyses. We also examined clinical data of the patients and their parents with SOX10 variants. RESULTS: Sequence analysis identified 2 heterozygous variants of SOX10 (c.1225G > T, p.Gly409* and c.475C > T, p.Arg159Trp) in patients 1–3, as well as in the parents of patients 1 and 3. The variants were assessed as pathogenic/likely pathogenic, according to the American College of Medical Genomics guidelines. Both variants lacked in vitro transactivating activity for the MITF promoter and exerted no dominant-negative effects. Patients 1–3 carried no pathogenic variants in other genes examined. The patients presented with typical KS, while such features were absent in the parents of patients 1 and 3. None of the 5 variant-positive individuals exhibited hypopigmentation, while 1 and 2 individuals exhibited complete and partial hearing loss, respectively. CONCLUSION: These results provide evidence that SOX10 haploinsufficiency accounts for a small percentage of KS cases. SOX10 haploinsufficiency is likely to be associated with a broad phenotypic spectrum, which includes KS without other clinical features of WS/PCWH. |
format | Online Article Text |
id | pubmed-8170842 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | Oxford University Press |
record_format | MEDLINE/PubMed |
spelling | pubmed-81708422021-06-04 SOX10 Mutation Screening for 117 Patients with Kallmann Syndrome Shima, Hirohito Tokuhiro, Etsuro Okamoto, Shingo Nagamori, Mariko Ogata, Tsutomu Narumi, Satoshi Nakamura, Akie Izumi, Yoko Jinno, Tomoko Suzuki, Erina Fukami, Maki J Endocr Soc Clinical Research Articles INTRODUCTION: Kallmann syndrome (KS) is a genetically heterogeneous condition characterized by hypogonadotropic hypogonadism (HH) and olfactory dysfunction. Although SOX10, a causative gene for Waardenburg syndrome (WS) and peripheral demyelinating neuropathy, central demyelination, WS, and Hirschsprung disease (PCWH) has previously been implicated in KS, the clinical significance of SOX10 variants as the cause of KS remains uncertain. PATIENTS AND METHODS: A total of 117 patients with KS underwent mutation screening of SOX10 and 14 other causative genes for KS/HH. Rare SOX10 variants were subjected to in silico and in vitro analyses. We also examined clinical data of the patients and their parents with SOX10 variants. RESULTS: Sequence analysis identified 2 heterozygous variants of SOX10 (c.1225G > T, p.Gly409* and c.475C > T, p.Arg159Trp) in patients 1–3, as well as in the parents of patients 1 and 3. The variants were assessed as pathogenic/likely pathogenic, according to the American College of Medical Genomics guidelines. Both variants lacked in vitro transactivating activity for the MITF promoter and exerted no dominant-negative effects. Patients 1–3 carried no pathogenic variants in other genes examined. The patients presented with typical KS, while such features were absent in the parents of patients 1 and 3. None of the 5 variant-positive individuals exhibited hypopigmentation, while 1 and 2 individuals exhibited complete and partial hearing loss, respectively. CONCLUSION: These results provide evidence that SOX10 haploinsufficiency accounts for a small percentage of KS cases. SOX10 haploinsufficiency is likely to be associated with a broad phenotypic spectrum, which includes KS without other clinical features of WS/PCWH. Oxford University Press 2021-03-30 /pmc/articles/PMC8170842/ /pubmed/34095692 http://dx.doi.org/10.1210/jendso/bvab056 Text en © The Author(s) 2021. Published by Oxford University Press on behalf of the Endocrine Society. https://creativecommons.org/licenses/by-nc-nd/4.0/This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs licence (http://creativecommons.org/licenses/by-nc-nd/4.0/ (https://creativecommons.org/licenses/by-nc-nd/4.0/) ), which permits non-commercial reproduction and distribution of the work, in any medium, provided the original work is not altered or transformed in any way, and that the work is properly cited. For commercial re-use, please contact journals.permissions@oup.com |
spellingShingle | Clinical Research Articles Shima, Hirohito Tokuhiro, Etsuro Okamoto, Shingo Nagamori, Mariko Ogata, Tsutomu Narumi, Satoshi Nakamura, Akie Izumi, Yoko Jinno, Tomoko Suzuki, Erina Fukami, Maki SOX10 Mutation Screening for 117 Patients with Kallmann Syndrome |
title |
SOX10 Mutation Screening for 117 Patients with Kallmann Syndrome |
title_full |
SOX10 Mutation Screening for 117 Patients with Kallmann Syndrome |
title_fullStr |
SOX10 Mutation Screening for 117 Patients with Kallmann Syndrome |
title_full_unstemmed |
SOX10 Mutation Screening for 117 Patients with Kallmann Syndrome |
title_short |
SOX10 Mutation Screening for 117 Patients with Kallmann Syndrome |
title_sort | sox10 mutation screening for 117 patients with kallmann syndrome |
topic | Clinical Research Articles |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8170842/ https://www.ncbi.nlm.nih.gov/pubmed/34095692 http://dx.doi.org/10.1210/jendso/bvab056 |
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