Spectrum of growth hormone receptor mutations and associated haplotypes in Laron syndrome.
Laron syndrome is a rare autosomal recessive disorder characterized by resistance to growth hormone (GH). In 10 patients of different ethnic origins, we have analyzed all the GH receptor (GHR)-coding exons along with their splice junctions and 6 intragenic polymorphic sites defining several GHR gene haplotypes. This allowed us to identify the mutations in the 20 chromosomes studied and to describe a new GHR haplotype. Eleven different mutations associated with various GHR haplotypes were observed; they included 3 nonsense mutations, 3 splice defects and 5 missense mutations. Of the 11 mutations, 8 were novel. All the mutations involved the exoplasmic domain of the receptor and all the missense mutations were clustered in a short polypeptide segment. Most of the missense mutations affected residues conserved among GHRs from different species and the related molecules that belong to the cytokine receptor superfamily. Adding to the 5 mutations so far described, these findings illustrate the allelic heterogeneity of this syndrome and document the independent origin of the molecular defects, all features of clinical relevance for genetic counselling.
Amselem
S
S
Laboratoire de Génétique Moléculaire, Institut National de la Santé et de la Recherche Médicale (INSERM) U.91, Hôpital Henri Mondor, Créteil, France.
Duquesnoy
P
P
Duriez
B
B
Dastot
F
F
Sobrier
M L
ML
Valleix
S
S
Goossens
M
M
D000483:Alleles; D000595:Amino Acid Sequence; D001483:Base Sequence; D004247:DNA / Q000235:genetics; D004252:DNA Mutational Analysis; D005091:Exons; D006130:Growth Disorders / Q000235:genetics*; D006239:Haplotypes / Q000235:genetics; D006801:Humans; D007438:Introns; D008969:Molecular Sequence Data; D017354:Point Mutation; D011986:Receptors, Somatotropin / Q000235:genetics*; D013577:Syndrome
D011986:Receptors, Somatotropin; D004247:DNA