A missense mutation in the vasopressin-neurophysin precursor gene cosegregates with human autosomal dominant neurohypophyseal diabetes insipidus.

Abstract

Familial neurohypophyseal diabetes insipidus in humans is a rare disease transmitted as an autosomal dominant trait. Affected individuals have very low or undetectable levels of circulating vasopressin and suffer from polydipsia and polyuria. An obvious candidate gene for the disease is the vasopressin‐neurophysin (AVP‐NP) precursor gene on human chromosome 20. The 2 kb gene with three exons encodes a composite precursor protein consisting of the neuropeptide vasopressin and two associated proteins, neurophysin and a glycopeptide. Cloning and nucleotide sequence analysis of both alleles of the AVP‐NP gene present in a Dutch ADNDI family reveals a point mutation in one allele of the affected family members. Comparison of the nucleotide sequences shows a G‐‐‐‐T transversion within the neurophysin‐encoding exon B. This missense mutation converts a highly conserved glycine (Gly17 of neurophysin) to a valine residue. RFLP analysis of six related family members indicates cosegregation of the mutant allele with the DI phenotype. The mutation is not present in 96 chromosomes of an unrelated control group. These data suggest that a single amino acid exchange within a highly conserved domain of the human vasopressin‐associated neurophysin is the primary cause of one form of ADNDI.

Tumour-specific arginine vasopressin promoter activation in small-cell lung cancer

“…No mutations relative to the previously published sequences (Sausville et al, 1985;Bahnsen et al, 1992) were identified. Restriction sites, in the primers or plasmid, were utilized for sub-cloning into chloramphenicol acetyl transferase (CAT) reporter constructs.…”

“…Although 1.2 kb of the 5′ promoter region for human AVP has been cloned and sequenced (Bahnsen et al, 1992), this has been only partially characterized and no SCLC-specific elements have been identified. We amplified this region by PCR, as described in detail in Methods and shown diagrammatically in Figure 1B.…”

Molecular basis of autosomal dominant neurohypophyseal diabetes insipidus. Cellular toxicity caused by the accumulation of mutant vasopressin precursors within the endoplasmic reticulum.

“…The disorder is transmitted in an autosomal dominant manner, and typically presents in early childhood, apparently reflecting the progressive loss of AVP secretion in response to increased serum osmolality (7,8). Numerous mutations within the AVP gene have been identified recently in patients with FNDI (6,(9)(10)(11)(12)(13)(14)(15)(16)(17)(18). The mutations are distributed throughout the precursor protein, and include missense mutations within the signal sequence (10,12,13,17), the AVP peptide (17a), and the NP domain (6,9,11,(14)(15)(16)18).…”

Familial neurohypophyseal diabetes insipidus due to a novel mutation in the arginine vasopressin–neurophysin II gene

“…In this study, we present the clinical features of two patients with neurohypophyseal DI, not related to the earlier described Dutch families with this disease (9,10), caused by a novel mutation in the AVP-NPII gene.…”