The overall research connected with the project is aimed at elucidating the molecular basis of a newly discovered and probably novel form of familial severe dwarfism (Dwarfism of Sindh). This syndrome serves as a genetic paradigm to elucidate genes important for the expression of growth hormone (GH). The molecular basis of familial or sporadic isolated GH deficiency is unknown in the majority of cases. Dwarfism of Sindh was first described in 1994 in Pakistan; it is of relatively recent emergence, with the oldest patient 28 years old. There is a high degree of consanguinity in the affected kindred, and the mode of inheritance appears autosomal recessive. The clinical phenotype is one of proportionate dwarfism, with adult heights ranging from 114 to 136 cm. The biochemical/endocrine phenotype is consistent with isolated growth hormone deficiency. The structural gene for GH is normal. Linkage analysis of several candidate genes showed that the dwarfed phenotype is highly linked to the GHRH receptor gene of chromosome 7. Subsequent molecular cloning and sequencing of the GHRH receptor gene idenitified a non-sense mutation which severely truncates the GHRH receptor as the molecular basis of this syndrome. It is proposed 1) to obtain information about pituitary size and configuration through MRI scanning, and 2) to evaluate the ultraidan GH secretory pattern in the hterozygote individuals who are short and have residual GH secretion. The former will give critical information about the role of GHRH and its receptor in the development of the pituitary and somatotrophs in humans. The latter will yield important clues about the effect of single gene dosage (and hence perhaps mild gene defects/mutations in the GHRH receptor) in the generation of GH insufficiency and short stature.
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