Identification of eight new mutations in familial neurogenic diabetes insipidus supports the concept that defective folding of the mutant provasopressin-neurophysin causes the disease

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

OSTI ID:134307

Rittig, S; Siggaard, C; Pedersen, E B ^[1]

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1. University Hospital in Aarhus (Denmark); and others

Familial neurogenic diabetes insipidus (FNDI) is an autosomal dominant disorder with a uniform phenotype characterized by polyuria, polydipsia and a severe deficiency of arginine vasopressin (AVP). These abnormalities develop postnatally and appear to be due to progressive degeneration of AVP producing neurons. Previous studies in 8 FNDI kindreds have identified 5 different mutations in the gene that codes for the AVP-neurophysin (NP) precursor, AVP-NP. Four kindreds had the same missense mutation in the part of exon 1 that codes for the C-terminal amino acid of the signal peptide (SP). The other 4 had different missense mutations or a codon deletion in exon 2 which codes for the highly conserved part of NP. In the present study, the AVP-NP genes from 8 other kindreds with FNDI were sequenced bidirectionally using sequence and single-stranded DNA amplified by PCR with biotinylated primers flanking each of the 3 exons. We find that each of the 8 kindreds has a different, previously unreported mutation in either the SP coding part of exon 1, in exon 2 or in the variable, NP-coding part of exon 3. Combining these 8 new mutations with the 5 described previously reveals a distribution pattern that corresponds closely to the domains involved in the mutually interactive processes of AVP binding, folding and dimerization of NP. Based on these findings and the clinical features of FNDI, we postulate that the precursors produced by the mutant alleles are cytotoxic because they do not fold or dimerize properly for subsequent packaging and processing.

• OSTI ID: 134307
• Report Number(s): CONF-941009--; CNN: A239.1397
• 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
CODONS
DETECTION
DNA SEQUENCING
DOMINANT MUTATIONS
ENDOCRINE DISEASES
EXONS
GENE MUTATIONS
GENES
GENETICS
HEREDITARY DISEASES
NUCLEOTIDES
PATIENTS
PHENOTYPE
POLYMERASE CHAIN REACTION
PROTEINS
VASOPRESSIN