Congenital Central Hypothyroidism due to Homozygous Thyrotropin β 313ΔT Mutation Is Caused by a Founder Effect

Neonatal TSH screening has been a major achievement for the early detection and treatment of primary congenital hypothyroidism. It nevertheless fails to reveal cases of central hypothyroidism caused by TSH levels in the low normal range. In the last 10 yr, homozygous mutations in the TSHβ-subunit gene have been recognized as a cause of central hypothyroidism with isolated TSH deficiency. The most frequent TSHβ mutation 313ΔT (C105V) has been described in six apparently unrelated families. We investigated the frequency and possible monophyletic origin of the different TSHβ 313ΔT alleles of the three affected families. Haplotype analysis of five polymorphic single-nucleotide polymorphism loci in the TSHβ region revealed the presence of seven different haplotypes in the general population. In all six parental lines, the mutation occurred on the same haplotype. Extending the haplotype by two flanking microsatellite markers led to a mutational age estimate of about 150 generations. In 500 unrelated individuals...

[1]  P. Beck‐Peccoz,et al.  Hyperplastic pituitary gland, high serum glycoprotein hormone alpha-subunit, and variable circulating thyrotropin (TSH) levels as hallmark of central hypothyroidism due to mutations of the TSH beta gene. , 2001, The Journal of clinical endocrinology and metabolism.

[2]  J. V. Moran,et al.  Initial sequencing and analysis of the human genome. , 2001, Nature.

[3]  J. Parma,et al.  Congenital central isolated hypothyroidism caused by a homozygous mutation in the TSH-beta subunit gene. , 2000, Thyroid : official journal of the American Thyroid Association.

[4]  A. Grüters,et al.  Severe Congenital Hypothyroidism Due to a Homozygous Mutation of the βTSH Gene , 1999, Pediatric Research.

[5]  L. Brooks,et al.  A DNA polymorphism discovery resource for research on human genetic variation. , 1998, Genome research.

[6]  J C Murray,et al.  Pediatrics and , 1998 .

[7]  R. Pfäffle,et al.  Congenital central hypothyroidism due to a homozygous mutation in the thyrotropin beta-subunit gene follows an autosomal recessive inheritance. , 1998, The Journal of clinical endocrinology and metabolism.

[8]  Cécile Fizames,et al.  A comprehensive genetic map of the human genome based on 5,264 microsatellites , 1996, Nature.

[9]  F. Wondisford,et al.  A circulating, biologically inactive thyrotropin caused by a mutation in the beta subunit gene. , 1996, The Journal of clinical investigation.

[10]  L. Excoffier,et al.  Maximum-likelihood estimation of molecular haplotype frequencies in a diploid population. , 1995, Molecular biology and evolution.

[11]  N. Risch,et al.  Genetic analysis of idiopathic torsion dystonia in Ashkenazi Jews and their recent descent from a small founder population , 1995, Nature Genetics.

[12]  A. Grüters,et al.  Etiological grouping of permanent congenital hypothyroidism with a thyroid gland in situ. , 1994, Hormone research.

[13]  G. Medeiros-Neto,et al.  Inherited Disorders of the Thyroid System , 1994 .

[14]  Cécile Fizames,et al.  The 1993–94 Généthon human genetic linkage map , 1994, Nature Genetics.

[15]  D. Styne.  Physiology of puberty. , 1994, Hormone Research.

[16]  I. Kourides,et al.  Familial hypothyroidism caused by a nonsense mutation in the thyroid-stimulating hormone beta-subunit gene. , 1990, American journal of human genetics.

[17]  A. Clark,et al.  Inference of haplotypes from PCR-amplified samples of diploid populations. , 1990, Molecular biology and evolution.

[18]  Y. Hayashizaki,et al.  Thyroid‐stimulating hormone (TSH) deficiency caused by a single base substitution in the CAGYC region of the beta‐subunit. , 1989, The EMBO journal.

[19]  D. Housman,et al.  Two thyroid hormone regulated genes, the beta-subunits of nerve growth factor (NGFB) and thyroid stimulating hormone (TSHB), are located less than 310 kb apart in both human and mouse genomes. , 1988, Genomics.

[20]  Francis S. Collins,et al.  Erratum: A DNA polymorphism discovery resource for research on human genetic variation (Genome Research (1998) 8 (1229-1231)) , 1999 .