ESPEYB21 6. Differences of Sexual Development (DSD) and Gender Incongruence (GI) DSD - Novel Genes and Mechanisms involved in Gonadal Development (4 abstracts)
6.2. Variants in SART3 cause a spliceosomopathy characterised by failure of testis development and neuronal defects
Ayers KL , Eggers S , Rollo BN , Smith KR , Davidson NM , Siddall NA , Zhao L , Bowles J , Weiss K , Zanni G , Burglen L , Ben-Shachar S , Rosensaft J , Raas-Rothschild A , Jørgensen A , Schittenhelm RB , Huang C , Robevska G , van den Bergen J , Casagranda F , Cyza J , Pachernegg S , Wright DK , Bahlo M , Oshlack A , O’Brien TJ , Kwan P , Koopman P , Hime GR , Girard N , Hoffmann C , Shilon Y , Zung A , Bertini E , Milh M , Ben Rhouma B , Belguith N , Bashamboo A , McElreavey K , Banne E , Weintrob N , BenZeev B & Sinclair AH
Nat Commun. 2023 Jun 9;14(1):3403. doi: 10.1038/s41467-023-39040-0. PMID: 37296101
Brief Summary: This translational study reveals a novel mechanism underlying syndromic gonadal dysgenesis (GD). It introduces a condition termed INDYGON syndrome (Intellectual disability, Neurodevelopmental defects and Developmental delay with 46,XY GONadal dysgenesis).
46,XY gonadal dysgenesis (GD) is a rare disorder of sex development (DSD) affecting 1-9 per 100,000 live births. Genetic diagnoses are achieved in less than half of cases despite advanced techniques. Many patients exhibit additional cardiac, renal, skeletal, and neurological abnormalities, classifying them as syndromic GD. Early molecular diagnosis is essential for timely detection and management of GD and associated comorbidities.
This multicenter study identified 9 individuals with biallelic “Squamous cell carcinoma antigen recognized by T cells 3” ( SART3 ) gene mutations. Five had 46,XY complete or partial GD, while the four 46,XX individuals had typical female genitalia and no reproductive disorders. All affected individuals exhibited neurodevelopmental defects, intellectual disability, hypotonia, craniofacial anomalies, corpus callosal agenesis or hypoplasia, ventriculomegaly, and cerebellar anomalies.
The spliceosome, essential for splicing non-coding introns from precursor mRNA, depends on the SART3 protein for recycling small nuclear RNAs (snRNAs). Ayers KL et al. demonstrated SART3’s conserved role in gonadal and neural development using a Drosophila model and testis-like organoids derived from human induced pluripotent stem cells (iPSCs) with patient-specific SART3 variants. In the RNAi-mediated SART3 orthologue knockdown Drosophila model, male flies were infertile, with disrupted spermatocytes, spermatids, and somatic cells, leading to immature, misshaped testes. Neuronal-specific knockdown caused complete embryonic lethality due to impaired neuronal development and midline defects.
Testis-like organoids homozygous for one of the human SART3 variants associated with XY GD were smaller with increased apoptosis. Transcriptomic analysis of SART3 variant iPSCs revealed alternative transcript usage in over 300 genes and widespread gene expression changes, including upregulation of many spliceosome components.
While further long-term studies are necessary to fully understand how gene-splicing abnormalities contribute to this condition, the identification of INDYGON syndrome underscores the critical role of spliceosome components like SART3 in both testicular and brain development.
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ESPE Yearbook of Paediatric Endocrinology
ISSN 1662-4009 (Online)
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