Two null alleles for the insulin receptor and a concomitant defect of the epidermal growth factor receptor in a severe form of leprechaunism

Journal Article · Thu Sep 01 04:00:00 EDT 1994 · American Journal of Human Genetics

OSTI ID:134251

Longo, N; Langley, S D; Griffin, L D; Elsas, L J ^[1]

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1. Emory Univ., Atlanta, GA (United States)

Leprechaunism is an autosomal recessive disorder caused by mutations in the insulin receptor gene and characterized by growth restriction and severe insulin-resistance. Here we report the characterization of a female patient, GE, who died at 7 weeks of age with a severe form of this syndrome. {sup 126}I-Insulin binding to fibroblasts from patient GE, her mother and father was reduced to 5, 40, and 28 percent of controls, respectively. Analysis of other tyrosine kinase receptors indicated that the proband`s cells had a concomitant defect in EGF binding, which was reduced to 20-40% of matched controls. Binding of IGF-I and PDGF-AA was normal in the proband`s cells. Defective EGF binding was due to decreased affinity for EGF (K{sub D} =6.8 nM, normal range 0.5-1.5 nM) with a minor reduction in the number of EGF binding sites. Reduced EGF binding in the proband`s fibroblasts was accompanied by decreased ability of EGF to simulate DNA synthesis and by reduced in vitro growth. EGF binding was normal in fibroblasts cultured from both parents. Analysis of the insulin receptor gene by PCR amplification using primers flanking each of the 22 exons and direct DNA sequencing identified two different mutations in patient GE. The paternal allele had a single nucleotide insertion in exon 10 which changed the codon for Thr 657 (ACC) to Asp (GAC) in the insulin repector cDNA. The resulting frame shift produced a premature STOP codon in position 665. The maternal mutation was an insertion of a single nucleotide in exon 10 which converted the codon for Cys 682 (TGC) to a STOP codon (TAG). We conclude that patient GE was a compound heterozygote for two null alleles in the insulin receptor gene. The concomitant partial defect in the EGF receptor may be secondary to the complete absence of functional insulin receptors which in turn may further impair growth.

• OSTI ID: 134251
• Report Number(s): CONF-941009--
• Journal Information: American Journal of Human Genetics, Journal Name: American Journal of Human Genetics Journal Issue: Suppl.3 Vol. 55; ISSN AJHGAG; ISSN 0002-9297
• Country of Publication: United States
• Language: English

Related Subjects

55 BIOLOGY AND MEDICINE
BASIC STUDIES
AMINO ACIDS
BIOSYNTHESIS
CODONS
DNA
DNA SEQUENCING
EPIDERMIS
EXONS
GENE MUTATIONS
GENES
GROWTH
GROWTH FACTORS
HEREDITARY DISEASES
INSULIN
NUCLEOTIDES
PATIENTS
PHOSPHOTRANSFERASES
POLYMERASE CHAIN REACTION
RECEPTORS
RECESSIVE MUTATIONS
TYROSINE