The pseudohypoparathyroidism type 1b locus is linked to a region including GNAS1 at 20q13.3

Pseudohypoparathyroidism (PHP) is characterized by biochemical hypoparathyroidism with elevated parathyroid hormone levels owing to reduced target tissue responsiveness to parathyroid hormone. Patients with PHP 1a have somatic defects termed Albright's hereditary osteodystrophy (AHO) and exhibit resistance to additional hormones because of heterozygous mutations in the GNAS1 gene that lead to a generalized deficiency of the α subunit of G_s, the heterotrimeric G protein that couples receptors to adenylyl cyclase. By contrast, patients with PHP 1b lack AHO and have selective parathyroid hormone (PTH) resistance, presumably because of an imprinting defect that impairs expression of G_sα in the proximal renal tubule. Although an epigenetic defect in GNAS1 has been identified in subjects with PHP1b, the genetic defect is unknown. To define the genetic defect in PHP 1b, we performed a genome-wide linkage analysis in five multi-generational PHP 1b families. Of the 408 polymorphic microsatellite markers examined, markers located on chromosome 20q13.3, the region containing GNAS1, demonstrated linkage to PHP 1b. Finemapping and multipoint linkage analysis of this region demonstrated linkage to a 5.7-cM region between 907rep2 and the telomere. Haplotype analysis established that affected individuals shared a 5-cM region including part of the GNAS1 gene to the telomere. Our data confirm that PHP1b is linked to a region that includes GNAS1, and further refine the locus, although the primary genetic mutation(s) that causes defective imprinting of GNAS1 remains undefined.