The Mouselysosomal membrane protein 1Gene as a Candidate for themotorneuron degeneration(mnd) Locus

Abstract

Themotorneuron degeneration(mnd) mutation causes one of the few late-onset progressive neurodegenerations in mice; therefore, themndmouse is a valuable paradigm for studying neurodegenerative biology. Themndmutation may also model human neuronal ceroid lipofuscinosis (NCL) or Batten disease.mndmaps to the centromeric region of mouse chromosome 8, which likely corresponds to portions of human chromosomes 13, 8, or 19; we note that the chromosome 13 portion maps close to a region thought to contain the human Type V NCL locus. We have identified candidate genes for themndlocus from human chromosomes 13, 8, and 19, and we are mapping these genes in the mouse to determine their proximity to the mutated locus and to refine the comparative human–mouse map in this area. A candidate gene from human chromosome 13 isLAMP1,which encodes lysosomal membrane protein 1. We found thatLamp1in the mouse lies within the region of themndmutation. Therefore, we sequencedLamp1cDNAs from homozygousmndmice and unrelated wildtype C57BL/6 mice. We find no differences between the two cDNA species in the regions examined, and expression analysis shows a similar LAMP1 protein distribution in wildtype and mutant mice, suggesting that an abnormal accumulation of material within normal lysosome structures is unlikely to be the pathogenetic mechanism in themndmouse.