THE DWARFS OF SINDH - SEVERE GROWTH-HORMONE (GH) DEFICIENCY CAUSED BYA MUTATION IN THE GH-RELEASING HORMONE-RECEPTOR GENE

We report the discovery of a cluster of severe familial dwarfism in tw o villages in the Province of Sindh in Pakistan. Dwarfism is proportio nate and occurs in members of a kindred with a high degree of consangu inity. Only the last generation is affected, with the oldest dwarf bei ng 28 years old. The mode of inheritance is autosomal recessive. Pheno type analysis and endocrine testing revealed isolated growth hormone d eficiency (GHD) as the reason for growth failure. Linkage analysis for the loci of several candidate genes yielded a high lod score for the growth hormone-releasing hormone receptor (GHRH-R) locus on chromosome 7. Amplification and sequencing of the GHRH-R gene in affected subjec ts demonstrated an amber nonsense mutation (GAG --> TAG; Glu(50) --> S top) in exon 3. The mutation, in its homozygous form, segregated 100% with the dwarf phenotype. it predicts a truncation of the GHRH-R in it s extracellular domain, which is likely to result in a severely disabl ed or non-existent receptor protein. Subjects who are heterozygous for the mutation show mild biochemical abnormalities in the growth hormon e-releasing hormone (GHRH)-growth hormone-insulin-like growth factor a xis, but have only minimal or no growth retardation. The occurrence of an offspring of two dwarfed parents indicates that the GHRH-R is not necessary for fertility in either sex. We conclude that Sindh dwarfism is caused by an inactivating mutation in the GHRH-R gene, resulting i n the inability to transmit a GHRH signal and consequent severe isolat ed GHD.