ESPEYB19 6. DSD and Gender Incongruence Basic and Genetic Research of DSD (6 abstracts)
6.6. Expanding DSD phenotypes associated with variants in the DEAH-box RNA helicase DHX37
Zidoune H , Martinerie L , Tan DS , Askari M , Rezgoune D , Ladjouze A , Boukri A , Benelmadani Y , Sifi K , Abadi N , Satta D , Rastari M , Seresht-Ahmadi M , Bignon-Topalovic J , Mazen I , Leger J , Simon D , Brauner R , Totonchi M , Jauch R , Bashamboo A & McElreavey K
Sex Dev. 2021;15(4):244-252. PMID: 34293745, doi: 10.1159/000515924.
Brief Summary: This genetic study provides data of a large cohort of 140 patients with DSD who were screened for DHX37 variants.
DHX37 emerges as a frequent cause of nonsyndromic 46,XY gonadal dysgenesis, and 46,XY testicular regression syndrome. Since the first description of the gene (1), DHX37 mutations were identified in 8-25% of some other groups of DSD patients (2,3). DHX37 encodes an RNA helicase protein (DEAH-box helicase 37) and its mutations impair ribosome biogenesis. Defects in ribosome assembly can cause a wide range of defined human diseases in specific cell types. DHX37 is one of the most highly conserved genes in the human genome and is intolerant to loss-of-function and missense variants in the general population. The mechanism, whereby a highly conserved ribosomal subunit can generate a specific “ribosomopathy” is unknown.
The authors identified 7 patients with DHX37 variants out of 140 patients with DSD (5% of the cohort). The spectrum of phenotypes ranged from a 46,XY female with complete gonadal dysgenesis to unilateral testicular regression in a fertile male. Unlike all previously reported heterozygous pathogenic DHX37 variants associated with 46,XY DSD, a boy with testicular regression who carried a homozygous DHX37 variant (c.C1430T) was identified.
Understanding precisely how DHX37 mutations lead specifically to DSD will serve as a paradigm for other ribosomopathies. According to the authors` hypothesis in this paper, 46,XY DSD caused by DHX37 variants is the result of increased nucleolar stress which causes a rapid and transient rise in WNT signaling leading to β-catenin stabilization. Inappropriate activation of the canonical WNT/β-catenin pathway favors the ovarian development and increased pro-ovary WNT-signaling in the somatic XY gonadal progenitor cells may be sufficient to disrupt testis determination.
References: 1. McElreavey K, Jorgensen A, Eozenou C, Merel T, Bignon-Topalovic J, Tan DS, Houzelstein D, Buonocore F, Warr N, Kay RGG, Peycelon M, Siffroi JP, Mazen I, Achermann JC, Shcherbak Y, Leger J, Sallai A, Carel JC, Martinerie L, Le Ru R, Conway GS, Mignot B, Van Maldergem L, Bertalan R, Globa E, Brauner R, Jauch R, Nef S, Greenfield A, Bashamboo A. Pathogenic variants in the DEAH-box RNA helicase DHX37 are a frequent cause of 46,XY gonadal dysgenesis and 46,XY testicular regression syndrome. Genet Med. 2020 Jan;22(1):150–159. doi: 10.1038/s41436-019-0606-y. PMID: 31337883. 2. da Silva TE, Gomes NL, Lerário AM, Keegan CE, Nishi MY, Carvalho FM, Vilain E, Barseghyan H, Martinez-Aguayo A, Forclaz MV, Papazian R, Pedroso de Paula LC, Costa EC, Carvalho LR, Jorge AAL, Elias FM, Mitchell R, Costa EMF, Mendonca BB, Domenice S. Genetic Evidence of the Association of DEAH-Box Helicase 37 Defects With 46,XY Gonadal Dysgenesis Spectrum. J Clin Endocrinol Metab. 2019 Dec 1;104(12):5923–5934. doi: 10.1210/jc.2019-00984. PMID: 31287541. 3. Buonocore F, Clifford-Mobley O, King TFJ, Striglioni N, Man E, Suntharalingham JP, Del Valle I, Lin L, Lagos CF, Rumsby G, Conway GS, Achermann JC. Next-Generation Sequencing Reveals Novel Genetic Variants (SRY, DMRT1, NR5A1, DHH, DHX37) in Adults With 46,XY DSD. J Endocr Soc. 2019 Oct 10;3(12):2341–2360. doi: 10.1210/js.2019-00306. PMID: 31745530; PMCID: PMC6855215.
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ESPE Yearbook of Paediatric Endocrinology
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