{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,23]],"date-time":"2026-04-23T04:17:17Z","timestamp":1776917837019,"version":"3.51.2"},"reference-count":17,"publisher":"Wiley","issue":"5","license":[{"start":{"date-parts":[[2017,8,13]],"date-time":"2017-08-13T00:00:00Z","timestamp":1502582400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/501100005736","name":"Universit\u00e9 Paris Diderot","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100005736","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100006319","name":"Centre National pour la Recherche Scientifique et Technique","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100006319","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100002915","name":"Fondation pour la Recherche M\u00e9dicale","doi-asserted-by":"publisher","award":["DEQ20150331757"],"award-info":[{"award-number":["DEQ20150331757"]}],"id":[{"id":"10.13039\/501100002915","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Clinical Endocrinology"],"published-print":{"date-parts":[[2017,11]]},"abstract":"<jats:title>Summary<\/jats:title><jats:sec><jats:title>Objective<\/jats:title><jats:p>Disorders of sex development (<jats:styled-content style=\"fixed-case\">DSD<\/jats:styled-content>) are a heterogeneous group of conditions affecting the differentiation and development of the internal and external genitalia. Here, we aimed at identifying the genetic cause of <jats:styled-content style=\"fixed-case\">DSD<\/jats:styled-content> in two 46,<jats:styled-content style=\"fixed-case\">XY<\/jats:styled-content> sisters from a consanguineous family.<\/jats:p><\/jats:sec><jats:sec><jats:title>Design<\/jats:title><jats:p>We performed a whole\u2010exome sequencing of two 46,<jats:styled-content style=\"fixed-case\">XY<\/jats:styled-content> female individuals. Sanger sequencing was used to validate the most likely candidate variant, affecting the desert hedgehog (<jats:italic><jats:styled-content style=\"fixed-case\">DHH<\/jats:styled-content><\/jats:italic>) gene. Molecular dynamics simulations were performed to get insights into the impact of the variant on protein structure and on its interaction with the protein partner <jats:styled-content style=\"fixed-case\">BOC<\/jats:styled-content> (brother of <jats:styled-content style=\"fixed-case\">CDO<\/jats:styled-content>\/cell adhesion molecule, downregulated by oncogenes).<\/jats:p><\/jats:sec><jats:sec><jats:title>Patients<\/jats:title><jats:p>The index patient presented with a female phenotype, primary amenorrhoea (low oestradiol and testosterone and high <jats:styled-content style=\"fixed-case\">FSH<\/jats:styled-content> and <jats:styled-content style=\"fixed-case\">LH<\/jats:styled-content>). She also had an apparent absence of intra\u2010abdominal gonads and uterus, facial dysmorphy, psychomotor retardation and neuropathy. Her sister displayed a similar gonadal and endocrinological picture, without dysmorphy or psychomotor retardation.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Whole\u2010exome sequencing revealed a homozygous variant in <jats:italic><jats:styled-content style=\"fixed-case\">DHH<\/jats:styled-content><\/jats:italic> leading to the p.Trp173Cys substitution. The relevant Trp residue is conserved, and its alteration was predicted to be deleterious. Molecular dynamics simulations showed that the mutation increases the conformational flexibility of the protein and potentially alters its interaction with <jats:styled-content style=\"fixed-case\">BOC<\/jats:styled-content>, a positive regulator of Hedgehog signalling. We do not exclude an interference of the mutation with <jats:styled-content style=\"fixed-case\">DHH<\/jats:styled-content>\u2010intein\u2010mediated auto\u2010processing.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>This report increases the number of described homozygous <jats:italic><jats:styled-content style=\"fixed-case\">DHH<\/jats:styled-content><\/jats:italic> variants and highlights the importance of advanced bioinformatic tools to better understand the pathogenicity of human variants.<\/jats:p><\/jats:sec>","DOI":"10.1111\/cen.13420","type":"journal-article","created":{"date-parts":[[2017,7,14]],"date-time":"2017-07-14T14:22:40Z","timestamp":1500042160000},"page":"539-544","source":"Crossref","is-referenced-by-count":21,"title":["A novel variant of <i><scp>DHH<\/scp><\/i> in a familial case of 46,<scp>XY<\/scp> disorder of sex development: Insights from molecular dynamics simulations"],"prefix":"10.1111","volume":"87","author":[{"given":"Francoise","family":"Paris","sequence":"first","affiliation":[{"name":"D\u00e9partement d'Endocrinologie et de Gyn\u00e9cologie P\u00e9diatriques CHU Arnaud de Villeneuve Universit\u00e9 de Montpellier  Montpellier France"},{"name":"D\u00e9partement d'Hormonologie CHU Lapeyronie Universit\u00e9 de Montpellier  Montpellier France"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Delphine","family":"Flatters","sequence":"additional","affiliation":[{"name":"Mol\u00e9cules Th\u00e9rapeutiques in Silico Inserm UMR\u2010S 973  Paris France"},{"name":"Universit\u00e9 Paris Diderot Sorbonne Paris Cit\u00e9  Paris France"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sandrine","family":"Caburet","sequence":"additional","affiliation":[{"name":"Universit\u00e9 Paris Diderot Sorbonne Paris Cit\u00e9  Paris France"},{"name":"Institut Jacques Monod Universit\u00e9 Paris Diderot CNRS UMR7592  Paris France"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"B\u00e9rang\u00e8re","family":"Legois","sequence":"additional","affiliation":[{"name":"Universit\u00e9 Paris Diderot Sorbonne Paris Cit\u00e9  Paris France"},{"name":"Institut Jacques Monod Universit\u00e9 Paris Diderot CNRS UMR7592  Paris France"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Nad\u00e8ge","family":"Servant","sequence":"additional","affiliation":[{"name":"D\u00e9partement d'Hormonologie CHU Lapeyronie Universit\u00e9 de Montpellier  Montpellier France"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Herv\u00e9","family":"Lefebvre","sequence":"additional","affiliation":[{"name":"Service d'Endocrinologie Diab\u00e8te et Maladies M\u00e9taboliques INSERM U1239 CHU de Rouen  Rouen France"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Charles","family":"Sultan","sequence":"additional","affiliation":[{"name":"D\u00e9partement d'Endocrinologie et de Gyn\u00e9cologie P\u00e9diatriques CHU Arnaud de Villeneuve Universit\u00e9 de Montpellier  Montpellier France"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4100-2681","authenticated-orcid":false,"given":"Reiner A.","family":"Veitia","sequence":"additional","affiliation":[{"name":"Universit\u00e9 Paris Diderot Sorbonne Paris Cit\u00e9  Paris France"},{"name":"Institut Jacques Monod Universit\u00e9 Paris Diderot CNRS UMR7592  Paris 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