Novel truncating thyroglobulin gene mutations associated with congenital hypothyroidism

Abstract

Mutations in the thyroglobulin (TG) gene have been reported to cause congenital hypothyroidism (CH) and we have been investigating the genetic architecture of CH in a large cohort of consanguineous/multi-case families. Our aim in this study was to determine the genetic basis of CH in four affected individuals coming from two separate consanguineous families. Since CH is usually inherited in autosomal recessive manner in consanguineous/multi-case families, we adopted a two-stage strategy of genetic linkage studies and targeted sequencing of the TG gene. First we investigated the potential genetic linkage of families to any known CH locus using microsatellite markers and then determined the pathogenic mutations in linked-genes by Sanger sequencing. Both families showed potential linkage to TG locus and we detected two previously unreported nonsense TG mutations (p.Q630X and p.W637X) that segregated with the disease status in both families. This study highlights the importance of molecular genetic studies in the definitive diagnosis and classification of CH, and also adds up to the limited number of nonsense TG mutations in the literature. It also suggests a new clinical testing strategy using next-generation sequencing in all primary CH cases.

Importance of molecular genetic analysis in the diagnosis and classification of congenital hypothyroidism

“…In addition to NMD pathway and ER storage diseases as pathophysiological mechanisms in the generation of CH, these truncated mutants have impairment in thyroid hormone synthesis. To complete this scenario, a second and remarkably finding was observed by Cangul et al [2], the two affected siblings with p.W637X mutation in the TG gene showed surprisingly thyroid hypoplasia. As mentioned above, the patients with TG deficiency have different degrees of goiter due to proliferative effect of the high and constant levels of TSH.…”

“…In neonates, a complete diagnosis of CH should include clinical examination, biochemical thyroid tests, ultrasound, and radioiodine or technetium scintigraphy. The article by Cangul et al [2] in this issue of Endocrine provides additional information about the clinical and genetic analyses from four new patients with CH, belonging to two unrelated consanguineous Turkish families, homozygous for nonsense mutations in the TG gene.…”

“…Cangul et al [2] describe the first report in which inactivating mutations in exon 9 was identified in the human TG gene and detected two new nonsense TG mutations: p.Q630X and p.W637X. Previously, a p.R697X mutation in the exon 9 of TG gene has been described in Afrikander cattle [7].…”

Novel compound heterozygous Thyroglobulin mutations c.745+1G>A/c.7036+2T>A associated with congenital goiter and hypothyroidism in a Vietnamese family. Identification of a new cryptic 5′ splice site in the exon 6

“…Several patients were identified with dyshormonogenesis caused by mutations in the TG gene (Abdul-Hassan et al, 2013;Agretti et al, 2013;Alzahrani et al, 2006;Cangul et al, 2014;Caputo et al, 2007aCaputo et al, , 2007bCaron et al, 2003;Citterio et al, 2011Citterio et al, , 2013aCitterio et al, , 2013bCorral et al, 1993;González-Sarmiento et al, 2001;Gutnisky et al, 2004;Hermanns et al, 2013;Hishinuma et al, 1999Hishinuma et al, , 2005Hishinuma et al, , 2006Ieiri et al, 1991;Kahara et al, 2012;Kanou et al, 2007;Kim et al, 2008;Kitanaka et al, 2006;Liu et al, 2012;Machiavelli et al, 2010;Moya et al, 2011;Narumi et al, 2011;Niu et al, 2009;Pardo et al, 2008Pardo et al, , 2009Pérez-Centeno et al, 1996;Peteiro-Gonzalez et al, 2010;Raef et al, 2010;Rivolta et al, 2005;Targovnik et al, 1993Targovnik et al, , 1995Targovnik et al, , 2001Targovnik et al, , 2010bTargovnik et al, , 2012van de Graaf et al, 1999). These defects are inherited in an autosomal recessive manner and affected individuals are either homozygous or compound heterozygous for the mutations.…”

Sterol regulatory element-binding proteins are transcriptional regulators of the thyroglobulin gene in thyroid cells

“…The initial iodination of TG leads to mono-and diiodotyrosine (MIT and DIT, respectively), and enzymatic coupling of the iodotyrosyl residues by TPO produces the TH [9]. The critical role of NIS, TPO and TG for TH synthesis is shown by the fact that genetic abnormalities in any of these key proteins leads to severe congenital hypothyroidism and goiter formation [10][11][12].…”