Homozygosity Mapping of Portuguese and Japanese Forms of Ataxia-Oculomotor Apraxia to 9p13, and Evidence for Genetic Heterogeneity

Abstract

Ataxia with oculomotor apraxia (AOA) is characterized by early-onset cerebellar ataxia, ocular apraxia, early areflexia, late peripheral neuropathy, slow progression, severe motor handicap, and absence of both telangiectasias and immunodeficiency. We studied 13 Portuguese families with AOA and found that the two largest families show linkage to 9p, with LOD scores of 4.13 and 3.82, respectively, at a recombination fraction of 0. These and three smaller families, all from northern Portugal, showed homozygosity and haplotype sharing over a 2-cM region on 9p13, demonstrating the existence of both a founding event and linkage to this locus, AOA1, in the five families. Three other families were excluded from this locus, demonstrating nonallelic heterogeneity in AOA. Early-onset cerebellar ataxia with hypoalbuminemia (EOCA-HA), so far described only in Japan, is characterized by marked cerebellar atrophy, peripheral neuropathy, mental retardation, and, occasionally, oculomotor apraxia. Two unrelated Japanese families with EOCA-HA were analyzed and appeared to show linkage to the AOA1 locus. Subsequently, hypoalbuminemia was found in all five Portuguese patients with AOA1 with a long disease duration, suggesting that AOA1 and EOCA-HA correspond to the same entity that accounts for a significant proportion of all recessive ataxias. The narrow localization of AOA1 should prompt the identification of the defective gene.

Cerebellar ataxia with oculomotor apraxia type 1: clinical and genetic studies

“…Hypoalbuminaemia and hypercholesterolaemia are often associated. A similar phenotype was described in several Portuguese families (Barbot et al, 2001) that enabled mapping of the locus designated AOA1 to chromosome 9p13 (Moreira et al, 2001a), followed by identi®cation of mutations in the APTX gene in both Japanese and Portuguese families (Moreira et al, 2001b;Date et al, 2001). The APTX gene encodes aprataxin, a histidine-triad (HIT) protein the function of which is still unknown.…”

A NovelGBA2Gene Missense Mutation in Spastic Ataxia

“…The APTX gene, mutations in which cause ataxia with oculomotor apraxia type 1 (AOA1) (Moreira et al, 2001), is located within the mapped region and has been excluded after thorough investigation. This finding was also in agreement with the absence of hypoalbuminaemia and hypercholesteronemia in the patients of this family as compared to other AOA1 patients.…”

The novel human gene aprataxin is directly involved in DNA single-strand-break repair

“…Genomic DNA was extracted from peripheral blood lymphocytes and all the APTX exons were amplified by PCR using the primers designed by Moreira et al [10]. Denaturing high-performance liquid chromatography (DHPLC) [20][21][22] was carried out on a 3500HT WAVE DNA fragment analysis system equipped with a DNASep column (Transgenomic).…”

“…polynucleotide kinase involved in the repair of both 3¢-phosphate and 5¢-hydroxyl termini after interaction with XRCC1 and other proteins of the DNA singlestrand-break repair (SSBR) pathway, thus suggesting a first link between APTX and SSBR [10]. More recently, aprataxin was shown to interact with the DNA repair proteins PARP-1, XRCC1 and p53, and to co-localize with XRCC1 along charged particle tracks on chromatin.…”