ABSTRACT
BACKGROUND: Congenital hypothyroidism is a frequent disease occurring with an incidence of about 1/1500 newborns/year. In about 75% of the cases, CH is caused by alterations in thyroid morphogenesis, defined "thyroid dysgenesis" (TD). TD is generally a sporadic disease but in about 5% of the cases a genetic origin has been demonstrated. Previous studies indicate that Dnajc17 as a candidate modifier gene for hypothyroidism, since it is expressed in the thyroid bud, interacts with NKX2.1 and PAX8 and it has been associated to the hypothyroid phenotype in mice carrying a single Nkx2.1 and Pax8 genes (double heterozygous knock-out). PURPOSE: The work evaluates the possible involvement of DNAJC17 in the pathogenesis of TD. METHODS: High-resolution DNA melting analysis (HRM) and direct sequencing have been used to screen for mutations in the DNAJC17 coding sequence in 89 patients with TD. RESULTS: Two mutations have been identified in the coding sequence of DNAJC17 gene, one in exon 5 (c.350A>C; rs79709714) and one in exon 9 (c.610G>C; rs117485355). The last one is a rare variant, while the rs79709714 is a polymorphism. Both are present in databases and the frequency of the alleles is not different between TD patients and controls. CONCLUSIONS: DNAJC17 mutations are not frequently present in patients with TD.
Subject(s)
Biomarkers/analysis , HSP40 Heat-Shock Proteins/genetics , Mutation , PAX8 Transcription Factor/genetics , Real-Time Polymerase Chain Reaction/methods , Thyroid Dysgenesis/genetics , Thyroid Nuclear Factor 1/genetics , Child , DNA Mutational Analysis , Female , Humans , Phenotype , Prognosis , Thyroid Dysgenesis/diagnosisABSTRACT
BACKGROUND: Congenital hypothyroidism (CH) is a frequent disease occurring with an incidence of about 1/2500 newborns/year. In 80-85% of the cases CH is caused by alterations in thyroid morphogenesis, generally indicated by the term "thyroid dysgenesis" (TD). TD is generally a sporadic disease, but in about 5% of the cases a genetic origin has been demonstrated. In these cases, mutations in genes playing a role during thyroid morphogenesis (NKX2-1, PAX8, FOXE1, NKX2-5, TSHR) have been reported. AIM: This work reviews the main steps of thyroid morphogenesis and all the genetic alterations associated with TD and published in the literature.
Subject(s)
Thyroid Dysgenesis/genetics , Thyroid Gland/embryology , Animals , Congenital Hypothyroidism/genetics , DNA-Binding Proteins/genetics , Female , Forkhead Transcription Factors/genetics , Homeobox Protein Nkx-2.5 , Homeodomain Proteins/genetics , Humans , Male , Mice , Nuclear Proteins/genetics , PAX8 Transcription Factor , Paired Box Transcription Factors/genetics , Receptors, Thyrotropin/genetics , Thyroid Nuclear Factor 1 , Transcription Factors/geneticsABSTRACT
CONTEXT: Congenital hypothyroidism (CH) is a common endocrine disorder with an incidence of 1:3000- 4000 newborns. In 80-85% of cases, CH is caused by defects in thyroid organogenesis, resulting in absent, ectopically located, and/or severely reduced gland, all conditions indicated as "thyroid dysgenesis" (TD). A higher prevalence of congenital heart diseases has been documented in children with CH compared to the general population. This association suggests a possible pathogenic role of genes involved in both heart and thyroid development. Among these, it can be included Isl1, a transcription factor containing a LIM homeodomain that is expressed in both thyroid and heart during morphogenesis. OBJECTIVE: In the present study, we investigate the role of ISL1 in the pathogenesis of TD. SETTINGS AND PATIENTS: By single stranded conformational polymorphism, we screened for mutations the entire ISL1 coding sequence in 96 patients with TD and in 96 normal controls. RESULTS: No mutations have been found in patients and controls. CONCLUSION: Our data indicate that, despite the relevant role of ISL1 in thyroid and heart morphogenesis, mutations in its coding region are not associated with TD in our group of patients.