ESPEYB17 3. Thyroid New genes (2 abstracts)
3.10. DGCR8 microprocessor defect characterizes familial multinodular goiter with schwannomatosis
Rivera B , Nadaf J , Fahiminiya S , Apellaniz-Ruiz M , Saskin A , Chong AS , Sharma S , Wagener R , Revil T , Condello V , Harra Z , Hamel N , Sabbaghian N , Muchantef K , Thomas C , de Kock L , Hébert-Blouin MN , Bassenden AV , Rabenstein H , Mete O , Paschke R , Pusztaszeri MP , Paulus W , Berghuis A , Ragoussis J , Nikiforov YE , Siebert R , Albrecht S , Turcotte R , Hasselblatt M , Fabian MR & Foulkes WD
To read the full abstract: J Clin Invest. 2020;130:1479–1490.
This detailed genetic and molecular analysis of a three-generation family reveals a new form of autosomal dominant tumor susceptibility syndrome entitled familial multinodular goiter (MNG) with schwannomatosis. Biallelic alterations of the DGCR8 gene were found in all affected patients: First, all patients harbored the same heterozygous germline mutation p.E518K. Secondly, all thyroid nodules and all schwannomas analyzed from the patients showed somatic loss of the whole chromosome 22 in addition to the p.E518K germline mutation, resulting in loss of heterozygosity. DGCR8 is key element of the canonical microRNA production pathway by forming a trimeric nuclear complex called microprocessor. The biallelic alteration of DGCR8 at the tumor tissue levels caused disrupted microprocessor function, resulting in reduced precursor and mature microRNA expression due to disrupted cleavage of precursor microRNA from primary RNA.
These data extend the spectrum of familial forms of MNG beside DICER1 syndrome, which was the first tumor susceptibility syndrome to include MNG [1–3], and reveal a striking mechanistic analogy between DGCR8 and DICER1 associated tumor syndromes: both genetic familial forms of MNG result from altered microRNA processing, however at different levels of the micro RNA production pathway. Whether disrupted microRNA biogenesis is involved in other MNG forms remains to be shown.
References:
1. de Kock L, Wu MK, Foulkes WD. Ten years of DICER1 mutations: Provenance, distribution, and associated phenotypes. Hum Mutat. 2019;40:1939–1953.
2. DICER1 mutations in familial pleuropulmonary blastoma. Hill DA, Ivanovich J, Priest JR, Gurnett CA, Dehner LP, Desruisseau D, Jarzembowski JA, Wikenheiser-Brokamp KA, Suarez BK, Whelan AJ, Williams G, Bracamontes D, Messinger Y, Goodfellow PJ. Science. 2009;325:965.
3. DICER1 mutations in familial multinodular goiter with and without ovarian Sertoli-Leydig cell tumors. Rio Frio T, Bahubeshi A, Kanellopoulou C, Hamel N, Niedziela M, Sabbaghian N, Pouchet C, Gilbert L, O’Brien PK, Serfas K, Broderick P, Houlston RS, Lesueur F, Bonora E, Muljo S, Schimke RN, Bouron-Dal Soglio D, Arseneau J, Schultz KA, Priest JR, Nguyen VH, Harach HR, Livingston DM, Foulkes WD, Tischkowitz M. JAMA. 2011;305:68–77.
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ESPE Yearbook of Paediatric Endocrinology
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