2 MUTANT ALLELES OF THE INSULIN-RECEPTOR GENE IN A FAMILY WITH A GENETIC FORM OF INSULIN-RESISTANCE - A 10-BASE-PAIR DELETION IN EXON-1 ANDA MUTATION SUBSTITUTING SERINE FOR ASPARAGINE-462

Citation
A. Cama et al., 2 MUTANT ALLELES OF THE INSULIN-RECEPTOR GENE IN A FAMILY WITH A GENETIC FORM OF INSULIN-RESISTANCE - A 10-BASE-PAIR DELETION IN EXON-1 ANDA MUTATION SUBSTITUTING SERINE FOR ASPARAGINE-462, Human genetics, 95(2), 1995, pp. 174-182
Citations number
32
Categorie Soggetti
Genetics & Heredity
Journal title
ISSN journal
03406717
Volume
95
Issue
2
Year of publication
1995
Pages
174 - 182
Database
ISI
SICI code
0340-6717(1995)95:2<174:2MAOTI>2.0.ZU;2-5
Abstract
Mutations in the insulin receptor gene cause several genetic syndromes associated with extreme insulin resistance. We have studied three ins ulin resistant siblings with acanthosis nigricans, dental abnormalitie s, and acral hypertrophy. The female patient also had primary amenorrh ea due to hyperandrogenism. All three patients were compound heterozyg otes with two mutant alleles of the insulin receptor gene. One allele had a 10-bp deletion in the region of exon 1 encoding the hydrophobic signal peptide; this leads to a frameshift and premature chain termina tion at codon 61. The deletion occurs at the site of a direct repeat o f a hexanucleotide sequence interrupted by a tetranucleotide sequence; the deletion may have resulted from recombination between the upstrea m and downstream hexanucleotide repeats. In the other mutant allele, t here is a missense mutation substituting serine for Asn(462) - a mutat ion identified previously in one allele of the insulin receptor gene i n a patient with type-A insulin resistance. The Ser(462) mutation impa ired the ability of acidic pH to dissociate insulin from the receptor. Thus, like the previously described Glu(460) mutation, the Ser(462) m utation may retard dissociation of insulin from the receptor in the ac idic compartment of the endosome and may, as a result, accelerate the rate of receptor degradation.