Giant Axonal Neuropathy Locus Refinement To A < 590 KB Critical Interval

Abstract

Giant axonal neuropathy (GAN) is a rare autosomal recessive neurodegenerative disorder, characterised clinically 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 CAN 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.…”

“…Numbering of families 9, 14, and 15 is according to Bomont et al (2000). The patients from these three families were shown to be homozygous for all 16q24.1 markers tested (12, 5 and 4 markers respectively; Cavalier et al, 2000;Bomont et al, 2000). Although the parents of family 15 are not consanguineous, they originate from the same mountainous village.…”

“…An abnormal accumulation of neurofilaments in the giant axons is an essential finding, and extends to other intermediate filaments and to a wide range of cells, including endothelial cells, Schwann cells, cultured skin fibroblasts, and astrocytes, suggesting a generalised disorganisation of the intermediate filament networks (Prineas et al, 1976;Pena, 1982;Kretzschmar et al, 1987;Buissonniere et al, 1989;Bousquet et al, 1996). We previously mapped the GAN locus on chromosome 16q24.1 (Ben Hamida et al, 1997;Cavalier et al, 2000) and identified the GAN gene (gb:AF291673), which encodes a 597 aa long novel protein of unknown function, that we named gigaxonin; AAG35311). Gigaxonin is formed of two domains, a N-terminus BTB/POZ domain, and a C-terminus Kelch repeat domain, but is only distantly related to other members of the BTB/Kelch repeat family precluding direct inference of its function.…”

Neurofilaments: neurobiological foundations for biomarker applications

“…A central role for E3-ligase activity in the turnover of NF was discovered through studies of GAN (Bomont et al, 2000), a fatal autosomal recessive neuropathy (Cavalier et al, 2000) in which giant axons (up to 50 μm in diameter) filled with densely packed and disorganized NF are found throughout the peripheral and central nervous system (Asbury et al, 1972). Starting early in infancy, the disease is associated with progressive loss of motor and sensory function (Johnson-Kerner et al, 2014).…”