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.

Figure 1

Simplified pedigrees of the families with AOA that show linkage to 9p13, and of family AOAP9. Markers are shown, from top to bottom, in their pter-qter order (from GeneMap'99). Haplotypes linked to the disease are boxed, and homozygosity in patients is shaded in gray. Distance (cM) to the previous marker is indicated before each marker (Fondation Jean Dausset–CEPH; The Sanger Centre). Markers that were part of the initial whole-genome screening are underlined. nt=not tested. The 5′ allele of D9S1791 is intermediate between alleles 5 and 6 (a single-nucleotide variation).

Figure 1

Simplified pedigrees of the families with AOA that show linkage to 9p13, and of family AOAP9. Markers are shown, from top to bottom, in their pter-qter order (from GeneMap'99). Haplotypes linked to the disease are boxed, and homozygosity in patients is shaded in gray. Distance (cM) to the previous marker is indicated before each marker (Fondation Jean Dausset–CEPH; The Sanger Centre). Markers that were part of the initial whole-genome screening are underlined. nt=not tested. The 5′ allele of D9S1791 is intermediate between alleles 5 and 6 (a single-nucleotide variation).

Figure 2

Haplotypes in families AOAP1, -P4, -P5, -P7, -P11, and -P9 and in AOAJ1 and -J2. Homozygous alleles are indicated only once per family. Alleles homozygous by descent are in boldface. The shared haplotypes are boxed and shaded in gray. Alleles that might belong to the founding haplotypes are boxed with dotted lines. Allele 13 from marker D9S1817 (in family AOAP5) might diverge from the founding haplotype by recombination or might derive from the founding allele (12) by slippage mutation of the marker. Phase in family AOAJ1 could not be inferred, since samples of the parents were not available. The dotted box above AOAJ1 and -J2 indicates that one haplotype of AOAJ1 might be identical to the homozygous AOAJ2 haplotype.

Figure 3

Geographical distribution, on the Portuguese mainland, of families with AOA. Districts where the survey is already completed are shaded in gray. Family AOAP13 is not represented, because of its African (Cabo Verde) origin. The three families in the Braga region that show linkage to 9p are AOAP4, -P7, and -P11, which share the largest region of linkage disequilibrium (fig. 2).