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Master Thesis

Pseudohypoparathyroïdie : distorsion du ratio de transmission maternelle des mutations perte de fonction de GNAS

Abstract : PseudoHypoParathyroidism Type 1A (PHP1A) and PseudoPseudoHypoParathyroidism (PPHP) are two rare autosomal dominant disorders caused by loss-of-function mutations in the imprinted GNAS gene, coding Gsα. PHP1A is caused by mutations in the maternal allele and results in Albright’s Hereditary Osteodystrophy (AHO) and PTH resistance, whereas PPHP, with AHO features and no hormonal resistance, is linked to mutations in the paternal allele. This study sought to investigate parental transmission of GNAS mutations. We conducted a retrospective study in a large population harboring GNAS mutations. To prevent ascertainment bias towards a higher proportion of affected children, we excluded from transmission analysis all probands in the ascertained sibships. The distribution ratio of the mutated alleles was calculated from the observed genotypes of the offspring of nuclear families and was compared to the expected ratio of 50% according to Mendelian inheritance (one-sample z-test). Transmission depending on the severity and phenotype of the transmitting parent of the mutation was also analyzed. The analysis was performed in 114 nuclear families and included 250 descendants. We showed an excess of transmission from mother to offspring of mutated alleles (59.0%, P=0.022), which was greater when the mutations were severe (61.7%, P=0.023), and when the allele originated from the grandmother (64.7%, P=0.036). A Mendelian distribution was observed when the mutations were paternally inherited. The mother-specific transmission ratio distortion associated to PHP1A points to a role of Gsα in oocyte biology or embryogenesis, with implications for genetic counselling.
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https://dumas.ccsd.cnrs.fr/dumas-02331048
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Sarah Snanoudj-Verber. Pseudohypoparathyroïdie : distorsion du ratio de transmission maternelle des mutations perte de fonction de GNAS. Médecine humaine et pathologie. 2019. ⟨dumas-02331048⟩

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