A null mutation in VAMP1/synaptobrevin is associated with neurological defects and prewean mortality in the lethal-wasting mouse mutant

• Published in: Neurogenetics Vol. 8; no. 1; pp. 1 - 10
• Main Authors: NYSTUEN, Arne M, SCHWENDINGER, Jamie K, SACHS, Andrew J, YANG, Andy W, HAIDER, Neena B
• Format: Journal Article
• Language: English
• Published: Berlin Springer 2007; Springer Nature B.V
• Subjects: Amino Acid Sequence; Animals; Biological and medical sciences; Brain - pathology; Chromosome Mapping; Codon, Nonsense; Disease Models, Animal; Epidemiology; Fundamental and applied biological sciences. Psychology; Gene expression; General aspects; Genetics of eukaryotes. Biological and molecular evolution; Genotype; Medical sciences; Mice; Mice, Neurologic Mutants; Molecular and cellular biology; Molecular Sequence Data; Mortality; Mutation; Nervous System Diseases - genetics; Nervous System Diseases - pathology; Neurology; Public health. Hygiene; Public health. Hygiene-occupational medicine; R-SNARE Proteins - genetics; Reverse Transcriptase Polymerase Chain Reaction; Rodents; Vertebrates: nervous system and sense organs; Vesicle-Associated Membrane Protein 1 - genetics; Wasting Syndrome - genetics; Wasting Syndrome - mortality; Wasting Syndrome - pathology; Nervous system diseases; Prognosis; Lethal-wasting mouse mutant; Mortality; Zona incerta; Rodentia; Nervous system; Identification; Complexes; Epidemiology; Neurology; Mutation identification; Vertebrata; Mammalia; Association; Mouse; Animal; Null mutation; Genetics; VAMP1; SNARE complex; Rostral periolivary region
• ISSN: 1364-6745; 1364-6753
• DOI: 10.1007/s10048-006-0068-7

The soluble N-ethylmaleimide sensitive factor attachment receptors are a large family of membrane-associated proteins that are critical for Ca(2+)-mediated synaptic vesicle release. This family includes the VAMP, synaptosomal-associated protein, and syntaxin proteins. In this report, we describe a mutation in vesicle-associated membrane protein 1(VAMP1)/synaptobrevin in the mouse neurological mutant lethal-wasting (lew). The lethal-wasting mutant phenotype is characterized by a general lack of movement and wasting, eventually leading to death before weaning. Mutants are visibly immobile and lay on their side by postnatal day 10 (P10). Before this stage, mutants can be identified by a failure to attempt to right themselves. Affected mice die on average at P15. We used a positional cloning strategy to identify the mutation associated with this neurological phenotype. Lethal wasting had previously been linked to chromosome 6. We further narrowed the genetic disease interval and selected a small number of candidate genes for mutation screening. Genes were evaluated by quantitative reverse transcription-polymerase chain reaction (RT-PCR) to detect differences in their expression levels between control and mutant brain ribonucleic acid (RNA) samples. VAMP1 mRNA was found to be significantly downregulated in the lethal-wasting brain compared to wild-type littermates. Subsequently, a nonsense mutation was identified in the coding region of the gene. This mutation is predicted to truncate approximately half of the protein; however, Western blot analysis showed that no protein is detectable in the mutant. VAMP1 is selectively expressed in the retina and in discrete areas of the brain including the zona incerta and rostral periolivary region, although no gross histological abnormalities were observed in these tissues. Taken together, these data indicate that VAMP1 has a vital role in a subset of central nervous system tissues.