Mutational Analysis of POLR3A and POLR3B Genes in Patients with 4H Syndrome and Isolated Hypogonadotropic Hypogonadism: Is There a Link Between These Two Conditions?

Program: Abstracts - Orals, Featured Poster Presentations, and Posters
Session: SAT 596-621-Pediatric Endocrinology /Steroids and Puberty
Saturday, June 15, 2013: 1:45 PM-3:45 PM
Expo Halls ABC (Moscone Center)

Poster Board SAT-606
Luciana Ribeiro Montenegro1, Marcela Rodríguez Freitas2, Ericka Barbosa Trarbach1, Milena Gurgel Teles1, Fernando Kok2, Ana Claudia Latronico1 and Leticia Gontijo Silveira*1
1Hospital das Clinicas da Faculdade de Medicina da Universidade de São Paulo, Sao Paulo, Brazil, 2Hospital das Clinicas, Faculdade de Medicina, Universidade de São Paulo, São Paulo, Brazil
Introduction: 4H syndrome is a RNA polymerase III-related leukodystrophy, characterized by progressive motor dysfunction, hypomyelinating leukodystrophy, hypogonadotropic hypogonadism and hypodontia. The 4H syndrome is a rare disorder, recently associated with biallelic mutations in POLR3A gene and, less commonly, in POLR3B. Congenital isolated hypogonadotropic hypogonadism (IHH) might represent a milder phenotypic variant of 4H syndrome and POLR3A and POLR3B could be involved in the pathogenesis of congenital IHH. Objective: To investigate POLR3A and POLR3B allelic variants in patients with 4H syndrome and IHH. Patients and methods: We studied seven patients with 4H syndrome (5 males) with variable degrees of cognitive impairment and motor dysfunction. All had hypomyelinating leukodystrophy at brain MRI. Hypodontia was present in five of them. Pubertal development was normal in one girl and one boy, a 22 yr female had confirmed IHH and four males, ranging from 10 to 16 yrs, were pre-pubertal. Eight congenital IHH patients (2 normosmic IHH and 6 Kallmann syndrome) were selected for a pilot study. Mutations in the known IHH genes had been previously excluded. The coding region of POLR3A and POLR3B was amplified from genomic DNA and automatically sequenced in the 4H syndrome patients. Only POLR3A was studied in IHH patients. Four softwares were used for in silico analysis of variants: Mutation Taster, PolyPhen-2, SIFT and Phanter. Results: The 4H syndrome female with IHH harbored compound heterozygous mutations in POLR3A (p.Ile34fs+p.Met852Val). One pre-pubertal 4H syndrome boy carried a heterozygous mutation in POLR3A (p.Ile952Val) and a heterozygous mutation in POLR3B (p.Thr862fs). Heterozygous POLR3A (p.Gln465* and p.His1286Gln) and POLR3B (p.Gln249*) variants were identified in 3 other 4H syndrome patients. No mutations were identified in the remaining two cases of 4H syndrome neither in the pilot IHH study group. In silico analysis of the variants suggested that all of them are deleterious, except for the p.Ile952Val. All variants were absent in the 1000 genome database. Conclusions: Mutations in POLR3A and/or POLR3B were identified in 71% of 4H syndrome cases, although in heterozygous state in the majority of them, and were more common in POLR3A than in POLR3B. Further studies with a larger number of patients are necessary to confirm if POLR3A and POLR3B variants can be associated with congenital IHH, without other typical features of 4H syndrome.

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