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
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
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.