Mutational analysis of TSC1 and TSC2 in Japanese patients with tuberous sclerosis complex revealed higher incidence of TSC1 patients than previously reported

Abstract

Tuberous sclerosis complex (TSC) is an autosomal dominant disorder characterized by multiple hamartias and hamartomas involving throughout the body. To date, many TSC1 and TSC2 mutations have been reported all over the world, however, few TSC mutation studies have been performed in the Japanese population, and genetic characteristics of Japanese TSC patients are not yet clear. In this study, we analyzed TSC1 and TSC2 in 57 Japanese patients with TSC (8 familial and 49 sporadic; 46 definite and 11 suspect TSC) and identified 31 mutations including 11 TSC1 mutations (two familial and nine sporadic; all definite TSC) and 20 TSC2 mutations (2 familial and 18 sporadic; 19 definite and 1 suspect TSC). We also reviewed all Japanese TSC mutations previously reported. Our study demonstrates significantly higher incidence (P=0.007) of TSC1 mutations among sporadic TSC patients in the Japanese population compared with US and European studies. No differences emerged in mutation distributions and types in precedent studies, excepting low frequency of the TSC2 nonsense mutation. Comparing clinical manifestations, developmental delay and/or mental retardation were milder in TSC1 patients than TSC2 patients for its frequency (P=0.032) and severity (P=0.015); however, no other symptoms were clearly different.

Mutational and functional study of Tuberous Sclerosis Complex 1 and 2 genes (TSC1 and TSC2)

“…Of note, 2.5% of TSC patients with a mutation identified had TSC2 deletions extending through PKD1 gene, defining cases with the contiguous gene deletion syndrome . Our data are similar to another Brazilian study as well as to reports from many countries , Chopra, Lawson et al 2011, Niida, Wakisaka et al 2013. Because our study does not aim to estimate the frequency of TSC in Brazil, we should not compare our data to previous reports that reported on the lack of ethnic or geographical bias of TSC distribution .…”

CHIPS for genetic testing to improve a regional clinical genetic service

“…We detected a total of nine mutations, of which six were not previously reported and one was previously reported by us , in addition to 31 polymorphisms. Actual working time to detect the mutation for each patient was just 2 days.…”

“…g), and clinically diagnosed as tuberous sclerosis complex (TSC). This couple hoped to have a biological child, and in TSC, it is known that TSC1 patients have lower risk of intellectual disability than TSC2 patients . So, the results of the genetic diagnosis affected their decision making.…”

Establishment of a Regional Interdisciplinary Medical System for Managing Patients with Tuberous Sclerosis Complex (TSC)

“…The functional complex of hamartin and tuberin acts as a GTPase that activates Ras homolog enriched in brain (Rheb) protein. Rheb-GTP activates mammalian target of rapamycin (mTOR), but the hamartin-tuberin complex suppresses mTOR activity by converting Rheb-GTP to Rheb-GDP 8 . Mutations in either TSC1 or TSC2 result in constitutive upregulation of the mTOR pathway, leading to hamartoma formation owing to the reduced function of this complex due to the gene mutation 9 .…”