| Added by | Cavailles |
|---|---|
| Group name | EquipeVC |
| Item Type | Journal Article |
| Title | A novel variant of DHH in a familial case of 46,XY disorder of sex development: Insights from molecular dynamics simulations |
| Creator | Paris et al. |
| Author | Delphine Flatters |
| Author | Sandrine Caburet |
| Author | Bérangère Legois |
| Author | Nadège Servant |
| Author | Hervé Lefebvre |
| Author | Charles Sultan |
| Author | Reiner A. Veitia |
| Abstract | OBJECTIVE: Disorders of sex development (DSD) 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 DSD in two 46,XY sisters from a consanguineous family. DESIGN: We performed a whole-exome sequencing of two 46,XY female individuals. Sanger sequencing was used to validate the most likely candidate variant, affecting the desert hedgehog (DHH) 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 BOC (brother of CDO/cell adhesion molecule, downregulated by oncogenes). PATIENTS: The index patient presented with a female phenotype, primary amenorrhoea (low oestradiol and testosterone and high FSH and LH). She also had an apparent absence of intra-abdominal gonads and uterus, facial dysmorphy, psychomotor retardation and neuropathy. Her sister displayed a similar gonadal and endocrinological picture, without dysmorphy or psychomotor retardation. RESULTS: Whole-exome sequencing revealed a homozygous variant in DHH 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 BOC, a positive regulator of Hedgehog signalling. We do not exclude an interference of the mutation with DHH-intein-mediated auto-processing. CONCLUSIONS: This report increases the number of described homozygous DHH variants and highlights the importance of advanced bioinformatic tools to better understand the pathogenicity of human variants. |
| Publication | Clinical Endocrinology |
| Volume | 87 |
| Issue | 5 |
| Pages | 539-544 |
| Date | Nov 2017 |
| Journal Abbr | Clin. Endocrinol. (Oxf) |
| Language | eng |
| DOI | 10.1111/cen.13420 |
| ISSN | 1365-2265 |
| Short Title | A novel variant of DHH in a familial case of 46,XY disorder of sex development |
| Library Catalog | PubMed |
| Extra | PMID: 28708305 |
| Tags | 46,XY DSD, Adult, Amino Acid Substitution, clinic, desert hedgehog, DHH, Disorder of Sex Development, 46,XY, Family Health, Female, Genetic Variation, gonadal dysgenesis, Hedgehog Proteins, Homozygote, Humans, Molecular Dynamics Simulation, Pedigree, Protein Conformation, Siblings |
| Date Added | 2019/05/16 - 15:12:31 |
| Date Modified | 2019/05/16 - 15:13:24 |
| Notes and Attachments | PubMed entry (Attachment) |
Institut de Recherche en Cancérologie de
