GH-releasing hormone receptor gene: a novel splice-disrupting mutation and study of founder effects.
BACKGROUND
Mutations in GH-releasing hormone receptor gene (GHRHR) are emerging as the most common cause of autosomal recessive isolated GH deficiency (IGHD).


OBJECTIVE
To search for GHRHR mutations in patients with familial or sporadic IGHD and to investigate founder effects in recurring mutations.


METHODS
The coding region of GHRHR was entirely amplified and sequenced from DNA of 18 patients with IGHD (16 unrelated) with topic posterior pituitary lobe on MRI. Haplotypes containing promoter SNPs and microsatellites flanking GHRHR were analyzed in patients with c.57+1G>A (IVS1+1G>A) mutation of our previously published kindred and also a Brazilian patient and 2 previously reported Japanese sisters with c.1146G>A (p.E382E) mutation.


RESULTS
A novel homozygous intronic GHRHR c.752-1G>A (IVS7-1G>A) mutation, predicting loss of the constitutive splice acceptor site, was identified in two siblings with IGHD. A compound heterozygous c.[57+1G>A];[1146G>A] and a heterozygous c.527C>T (p.A176V) were found in two sporadic cases. Haplotype analysis provided evidence for a founder effect for the c.57+1G>A mutation and independent recurrence for the c.1146G>A mutation.


CONCLUSIONS
We report a novel splice-disrupting mutation in GHRHR in 2 siblings and provide evidence that all c.57+1G>A (IVS1+1G>A) mutant chromosomes have the same haplotype ancestor, indicating the occurrence of a founder effect in Brazilian patients with IGHD.
Unidade de Endocrinologia do Desenvolvimento, Laboratório de Hormônios e Genética Molecular, São Paulo, Brazil. suemimar@usp.br
Suemi
S
Marui
Ericka B
EB
Trarbach
Margaret C S
MC
Boguszewski
Marcela M
MM
França
Alexander A L
AA
Jorge
Hiroshi
H
Inoue
Mirian Y
MY
Nishi
Luiz
L
de Lacerda Filho
Manuel H
MH
Aguiar-Oliveira
Berenice B
BB
Mendonca
Ivo J P
IJ
Arnhold
D000293:Adolescent; D001938:Brazil; D002648:Child; D002675:Child, Preschool; D004252:DNA Mutational Analysis; D004393:Dwarfism, Pituitary / Q000235:genetics; D005260:Female; D018703:Founder Effect; D006801:Humans; D008297:Male; D009154:Mutation; D022821:RNA Splice Sites / Q000235:genetics*; D012326:RNA Splicing / Q000235:genetics*; D018013:Receptors, Neuropeptide / Q000235:genetics*; D018017:Receptors, Pituitary Hormone-Regulating Hormone / Q000235:genetics*
D022821:RNA Splice Sites; D018013:Receptors, Neuropeptide; D018017:Receptors, Pituitary Hormone-Regulating Hormone; C048250:somatotropin releasing hormone receptor