Familial Dwarfism due to a Novel Mutation of the Growth Hormone-Releasing Hormone Receptor Gene¹

Abstract

Isolated growth hormone (GH) deficiency (IGHD) is a rare cause of short stature. The same mutation of the gene encoding the growth hormone-releasing hormone receptor (GHRHR) has been identified as the basis for IGHD in three families from the Indian subcontinent. The prevalence and heterogeneity of defects in the GHRHR gene are not known. Twenty-two dwarf members of a large, extended kindred containing at least 105 affected members with autosomal recessive short stature underwent extensive endocrine evaluation, which confirmed markedly reduced or undetectable serum concentrations of GH that did not increase in response to different stimuli. DNA sequences of the 13 exons and intron-exon boundaries of the GHRHR gene were determined in an index patient. A novel homozygous 5' splice site mutation (G-->A at position +1) in IVS1 was found. Thirty of the affected subjects tested were homozygous for this mutation, and 64 clinically unaffected patients were either heterozygous for the mutation (n = 41, including 9 obligate carriers) or homozygous for the wild-type sequence (n = 23). We describe a novel mutation in the GHRHR gene as cause of dwarfism in the largest kindred with familial IGHD described to date.

A new missense mutation in the growth hormone-releasing hormone receptor gene in familial isolated GH deficiency

“…The 13 exons, the corresponding intron-exon boundaries and the proximal part (327 bp) of the GHRHR gene were individually amplified via PCR using primers and conditions described previously (5). One primer of each pair contained a 5 0 GC-rich sequence 40 bases long, to increase the sensitivity of mutation detection via denaturing gradient gel electrophoresis (DGGE) (10 -12).…”

Serum GH response to pharmacological stimuli and physical exercise in two siblings with two new inactivating mutations in the GH-releasing hormone receptor gene

“…Although these results do not allow us to draw any definitive conclusion, this initial observation creates the rationale for studying GH response to PE in larger kindreds with mutated GHRHR, such as the ones from Brazil and Pakistan (5,6), where the high number of subjects may allow us to determine if any difference in GH secretion after PE and chemical secretagogues is real.…”

“…The 13 exons and the corresponding intron -exon boundaries and the proximal 327 bases of the promoter of the GHRHR from the index case (II-1) were individually amplified via PCR as in previous studies (6,7). PCR products were separated by electrophoresis through 8% acrylamide gels, and bands were isolated and sequenced directly.…”

MECHANISMS IN ENDOCRINOLOGY: The multiple facets of GHRH/GH/IGF-I axis: lessons from lifetime, untreated, isolated GH deficiency due to a GHRH receptor gene mutation

“…OMIM n. 612781). Most of the affected patients reside in the rural county of Itabaianinha, in the northeastern Brazilian state of Sergipe (2). Sergipe is the smallest state in Brazil.…”

“…Due to its smallness, it is linked to GH disorders since 1890, when de Souza leite, born there, presented together with Pierre Marie, the first descriptions of GH excess syndrome (3). Since 1994 we have been studying the other side of this spectrum, a cohort of 105 (some deceased) subjects with mostly untreated IGHD, exhibiting a pattern of recessive heritage in a pedigree traced back 200 years, including 1570 individuals in eight generations (2). The high frequency of consanguineous unions and the lack of mobility of this population were the principal causes for the spread of this mutation.…”