Giant axonal neuropathy locus refinement to a < 590 kb critical interval

Abstract

Giant axonal neuropathy (GAN) is a rare autosomal recessive neurodegenerative disorder, characterisedclinically by the development of chronic distal polyneuropathy during childhood, mental retardation, kinky or curly hair, skeletal abnormalities and, ultrastructurally, by axons in the central and peripheral nervous systems distended by masses of tightly woven neurofilaments. We recently localised the GAN locus in 16q24.1 to a 5-cM interval between the D16S507 and D16S511 markers by homozygosity mapping in three consanguineous Tunisian families. We have now established a contig-based physical map of the region comprising YACs and BACs where we have placed four genes, ten ESTs, three STSs and two additional microsatellite markers, and where we have identified six new SSCP polymorphisms and six new microsatellite markers. Using these markers, we have refined the position of our previous flanking recombinants. We also identified a shared haplotype between two Tunisian families and a small region of homozygosity in a Turkish family with distant consanguinity, both suggesting the occurrence of historic recombinations and supporting the conclusions based on the phase-known recombinations. Taken together, these results allow us to establish a transcription map of the region, and to narrow down the GAN position to a < 590 kb critical interval, an important step toward the identification of the defective gene.

Identification of seven novel mutations in theGAN gene

“…Linkage of families 9, 14, and 15 to the GAN locus was previously demonstrated by homozygosity mapping Cavalier et al, 2000). Genetic studies of family 16 with polymorphic markers LC8, LC6, D16S3098, GAAT2CO8 and D16S505 demonstrated linkage to 16p24.1 with a LOD score of 3.1 at θ = 0 (Fig.…”

Giant axonal neuropathy: clinical and genetic study in six cases

“…The three families affected by GAN were genotyped with polymorphic markers present in the GAN region on chromosome 16q24.1 (LC8, LC6, LC5, D16S3098, LC1, LC3, LC2, and D16S505). 13 Forward primers were labelled with 6-Fam, Hex, or Ned fluorochromes (Applied Biosystems Inc, Foster City, California, USA). Polymerase chain reactions (PCRs) were performed in a final volume of 10 ml containing 20 ng of genomic DNA, 1mM dNTP, 16 NBL buffer, 0.50mM of each primer, and 0.1 IU of Taq polymerase.…”

“…An aggregation of cytoplasmic intermediate filaments was also seen in other cell types, including fibroblasts, endothelial cells, melanocytes, and Langerhans cells, indicating a generalised disorganisation of cytoplasmic intermediate filaments in GAN. 9 10 We and others have located the GAN disease locus to 16q24.1 by homozygosity mapping in consanguineous families, [11][12][13] and we have recently identified the defective gene by positional cloning. 14 We found one single nucleotide insertion, nine missense, and four nonsense mutations, distributed throughout the 11 exons of the GAN gene, in 12 families of various origins.…”

Giant axonal neuropathy–associated gigaxonin mutations impair intermediate filament protein degradation

“…GAN is a recessive disease (4,5,16,17) caused by mutations in the GAN gene (encoding for gigaxonin), which is located on chromosome 16q24. Over 30 distinct mutations distributed throughout the GAN gene have been identified (9,11,16).…”