The gene responsible for pseudohypoparathyroidism type Ib is paternally imprinted and maps in four unrelated kindreds to chromosome 20q13.3

Abstract

Hypocalcemia and hyperphosphatemia caused by parathyroid hormone (PTH)-resistance are the only discernible abnormalities in pseudohypoparathyroidism type Ib (PHP-Ib). Because mutations in the PTH/PTH-related peptide receptor, a plausible candidate gene, had been excluded previously, we conducted a genome-wide search with four PHP-Ib kindreds and established linkage to a small telomeric region on chromosome 20q, which contains the stimulatory G protein gene. We, furthermore, showed that the genetic defect is imprinted paternally and thus is inherited in the same mode as the PTH-resistant hypocalcemia in kindreds with PHP-Ia and/or pseudo-pseudohypoparathyroidism, two related disorders caused by different stimulatory G protein mutations.

Figure 1

(A–D) Laboratory findings and haplotype analysis for markers on the telomeric end of chromosome 20q13. Most laboratory results of individuals affected by PHP-Ib were obtained at the time of diagnosis, and all other results were obtained for the present study; adult normal range for calcium is 2.15–2.60 mmol/liter, and for phosphate is 0.80–1.50 mmol/liter; phosphate measurements in children are shown in italics (pediatric normal range is 1.30–1.80 mmol/liter); normal range for PTH is indicated for each kindred; results obtained with earlier radioimmunoassay systems are shown in italics (respective normal range in parenthesis underneath). n.d., not determined; nl, within normal limits. The haplotype associated with the disorder is shown in bold and is highlighted by shading; recombinations in the allele inherited from obligate gene carriers are indicated by –; markers within the linked region are in bold; • or ■ and bold identification numbers, affected individuals; ○ or □ and regular numbers, healthy individuals; or ▧ and bold italic numbers, unaffected obligate gene carriers; and or ▧ and italic numbers, individuals identified in this study as carriers of the disease haplotype; individuals that were not available for testing and are affected or unaffected by history only are depicted by small symbols; some individuals were tested only for laboratory abnormalities (an asterisk next to a small symbol); \, deceased individual.

Figure 2

Schematic presentation of chromosome 20 and the region linked to PHP-Ib. The linked region is indicated (■), and the locations of microsatellite markers are based on mapping data produced by the Chromosome 20 Mapping Group at the Sanger Centre, Cambridge, U.K. (www.sanger.ac.uk/HGP/Chr20) and the Whitehead Institute, Cambridge, MA (www.genome.wi.mit.edu), by haplotype analysis of the four PHP-Ib kindreds (see Fig. 1 A–D), and by Southern blot analysis of selected PAC clones provided by the Sanger Centre (see Results for details).