title: Phenotypic and molecular genetic aspects of pseudohypoparathyroidism type Ib in a Greek kindred: evidence for enhanced uric acid excretion due to parathyroid hormone resistance.
abstract: The predominant feature of pseudohypoparathyroidism (PHP) is renal resistance to PTH. Pseudohypoparathyroidism type Ia (PHP-Ia) is caused by maternally inherited heterozygous mutations in the GNAS exons encoding the alpha-subunit of the stimulatory G protein (Gsalpha). Besides PTH resistance, PHP-Ia patients have Albright's hereditary osteodystrophy and often display resistance to additional hormones. Patients with PHP-Ib lack features of Albright's hereditary osteodystrophy, and PTH resistance is associated with loss of methylation at the maternal GNAS exon A/B. Most individuals with the autosomal dominant form of PHP-Ib have a 3-kb microdeletion within STX16 approximately 220 kb upstream of exon A/B. Here we report on the clinical and genetic aspects of a Greek PHP-Ib kindred with four affected members and three obligate carriers, who had the 3-kb deletion within STX16. Symptomatic hypocalcemia was present only in the proband, but PTH was elevated in all members who had inherited the 3-kb deletion maternally. In all affected family members, urinary phosphate excretion was normal, but 1,25-dihydroxyvitamin D levels were diminished. These findings confirm previous data regarding patient to patient variation in disease severity for autosomal dominant PHP-Ib. Furthermore, affected individuals displayed hypouricemia with increased fractional excretion of uric acid, suggesting possible involvement of PTH in the renal handling of this metabolite.
authors.affiliation: Department of Medicine, Division of Endocrinology, University of Ioannina, 45110 Ioannina, Greece.
authors.forename: Elena
authors.initials: E
authors.lastname: Laspa
authors.forename: Murat
authors.initials: M
authors.lastname: Bastepe
authors.forename: Harald
authors.initials: H
authors.lastname: Jüppner
authors.forename: Agathocles
authors.initials: A
authors.lastname: Tsatsoulis
mesh_terms: D000328:Adult; D002864:Chromogranins; D002890:Chromosomes, Human, Pair 20; D004351:Drug Resistance; D019205:GTP-Binding Protein alpha Subunits, Gs / Q000235:genetics; D008040:Genetic Linkage; D006115:Greece; D006801:Humans; D008297:Male; D008967:Molecular Biology; D010281:Parathyroid Hormone / Q000378:metabolism*; D010375:Pedigree; D010641:Phenotype; D011547:Pseudohypoparathyroidism / Q000097:blood / Q000235:genetics* / Q000503:physiopathology / Q000652:urine; D014527:Uric Acid / Q000097:blood / Q000652:urine*; D014807:Vitamin D / Q000031:analogs & derivatives* / Q000652:urine
chemical_list: D002864:Chromogranins; D010281:Parathyroid Hormone; D014807:Vitamin D; D014527:Uric Acid; C097949:1,25-dihydroxyvitamin D; C406732:GNAS protein, human; D019205:GTP-Binding Protein alpha Subunits, Gs