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Background: Thyroglobulin (TG) defect is a rare cause of congenital hypothyroidism. Although only 44 mutations of the human TG gene have been identified, we have suspected a TG defect in 38% of Taiwan Chinese children/adolescents presenting with moderate or severe thyroidal dyshormonogenesis., Study Objective: The aim of the study is to report the discovery of new TG gene mutations and associated clinical manifestations of the defective TG protein., Patients and Results: In seven patients from six families, we detected six new TG gene mutations, including c.1348delT, p.R432X (c.1351C>T), g.IVS3 + 2T>G, c.1712delT, p.Q1765X (c.5350C>T), and c.6047delA. The c.1348delT and p.R432X mutations were the most common, detected in 33 and 25%, respectively, of alleles studied. Haplotype analysis suggested that the c.1348delT and g.IVS3 + 2T>G mutations are due to founder effects, whereas p.R432X is probably due to independently recurrent de novo mutations. mRNA transcript of the g.IVS3 + 2T>G mutant, detected in whole blood by reverse transcription-nested PCR, showed skipping of exon 3 (98-bp deletion) and a frameshift, with a terminal signal after 17 altered amino acid residues., Conclusions: TG defects have an important role in severe thyroidal dyshormonogenesis (pretreatment, or after a 3-wk T(4) withdrawal, plasma T(4) < or = 30 nmol/liter) in Taiwanese. Its genetic characteristics are markedly different from those described in other populations presenting with mutations of the TG gene.

Context: Mutations that inactivate one allele of the gene encoding the calcium sensing receptor (CaSR) cause autosomal dominant familial hypocalciuric hypercalcemia (FHH), whereas homozygous mutations cause neonatal severe hyperparathyroidism., Objective: We describe the identification and biochemical characterization of a novel CASR gene mutation that caused apparent autosomal recessive FHH in an extended consanguineous kindred., Design: The study design involved direct sequence analysis of the CaSR gene, clinical and biochemical analyses of patients, and in vitro immunobiochemical studies of the mutant CaSR., Results: A novel inactivating mutation (Q459R) was identified in exon 4 of both alleles of the CASR in the proband, who presented with asymptomatic hypercalcemia and hypocalciuria at age 2 yr. The proband's parents were heterozygous for the Q459R mutation consistent with autosomal recessive inheritance of FHH. Among 13 family members that were studied, eight subjects were heterozygous for the Q459R mutation and five had normal genotypes. All heterozygous subjects were asymptomatic and normocalcemic apart from one subject who was mildly hypercalcemic. The Q459R mutant CaSR was normally expressed at the cell membrane but retained only 30-50% of the calcium-dependent activity of the wild-type CaSR., Conclusion: We identified a novel loss-of-function Q459R mutation in the CASR gene that exhibits mildly reduced sensitivity to calcium and that is associated with apparent autosomal recessive transmission of FHH. This study demonstrates the importance of genetic testing in FHH to distinguish between de novo and inherited mutations of the CASR gene and assist in management decisions.

Familial hypocalciuric hypercalcemia (FHH) is an autosomal dominant disorder characterized by high penetrance of relatively benign, lifelong persistent hypercalcemia and hypocalciuria. By contrast, neonatal severe hyperparathyroidism represents a life-threatening form of hypercalcemia that can cause the early newborn mortality if immediate intervention is not undertaken. Both disorders are due to inactivation mutation of the human calcium-sensing receptor (CaSR) gene on chromosome 3q21-24. Up to now, more than 30 mutations in the CaSR gene associated with FHH have been described. In this study, we analyzed one 79-yr-old male with hypocalciuric hypercalcemia without siblings or children to compare with an additional group of 50 normal Chinese subjects in Taiwan. DNA sequence analysis of the CaSR gene was performed. The result showed that the proband had a heterozygous nonsense mutation in exon 7 of the CaSR gene at codon 648 (CGA-->TGA/Arg-->Ter). This mutation, located in the COOH-terminal of the first intracellular loop of the CaSR, predicts a markedly truncated protein. We have identified a novel R648X mutation in the CaSR gene in one patient with FHH in Taiwan

Multiple hormone resistance in many patients with pseudohypoparathyroidism (PHP) type Ia and Albright's hereditary osteodystrophy (AHO) is associated with deficient activity of the stimulatory guanine nucleotide-binding protein (Gs) of adenylate cyclase. To study further the relationship of deficient Gs activity to hormone resistance, we evaluated endocrine function and measured Gs activity of erythrocyte membranes from AHO patients with clinical hormone resistance (PHP type Ia) and from family members with AHO alone (pseudopseudohypoparathyroidism). The results of erythrocyte membrane Gs determinations were compared to those of unaffected relatives and normal subjects. Patients with pseudopseudohypoparathyroidism (pseudoPHP) had reductions in erythrocyte membrane Gs activity comparable to those in patients with PHP type Ia [43.4 +/- 11.9% (+/- SD) for PHP type Ia vs. 47.8 +/- 9.5% for pseudoPHP]. However, in contradistinction to patients with PHP type Ia, individuals with pseudoPHP did not have obvious endocrine dysfunction. Although deficient Gs activity appears to play an important role in the pathogenesis of these disorders, it is possible that Gs deficiency must be combined with other factors that limit cAMP production to cause clinically overt endocrine disease.