Gene in the region of the Friedreich ataxia locus encodes a putative transmembrane protein expressed in the nervous system.

Abstract

Friedreich ataxia (FRDA) is an autosomal recessive degenerative disorder that affects the cerebellum, spinal cord, and peripheral nerves. The FRDA gene was localized in 9q13-q21 within 0.7 centimorgan of the D9SS and D9S15 loci. One recently reported recombination event and haplotype analysis in a population with a founder effect suggested that the FRDA locus is on the D9S5 side. Using a conserved probe from the D9SS locus, we have now identified an -7-kilobase (kb) transcript and report cloning of its cDNA. The corresponding gene, XlI, extends at least 80 kb in a direction opposite D9S15. The gene is expressed in the brain, including the cerebellum, but is not detectable in several nonneuronal tissues and cell lines. In situ hybridization of adult mouse brain sections showed prominant expression in the granular layer of the cerebellum. Expression was also found in the spinal cord. The cDNA contains an open reading frame encoding a 708-amino acid sequence that shows no significant similarity to other known proteins but contains a unique, 24-residue-long, putative transmembrane segment. On the basis of its genomic localization and its neuronal site of expression, particularly in the cerebellum, this "pioneer'" gene represents a candidate for FRDA. Direct evidence of its involvement in FRDA will require a search for causative point mutations in patients.Friedreich ataxia (FRDA) is a degenerative disorder involving both the central and peripheral nervous systems (1). It is characterized by progressive gait and limb ataxia, loss of position and vibration sense, loss of tendon reflexes in the lower limbs, and dysarthria. Neurological symptoms correlate with degeneration in the dorsal root ganglia, the posterior columns and spinocerebellar tracts ofthe spinal cord, and the cerebellum. In peripheral nerves, severe loss of thick myelinated fibers is found. Other symptoms are frequently found and usually occur as the disease progresses: pyramidal weakness of the legs, Babinski sign, scoliosis, cardiomyopathy, and pes cavus. An increased risk of diabetes mellitus seems to be associated with the disease. The primary defect underlying the selective cellular degeneration in FRDA remains unknown but the inherited nature of the disease (autosomal recessive) should allow identification ofthe defective gene by positional cloning. The FRDA gene was localized on chromosome 9 in 1988 (2) and extensive genetic and physical mapping of the locus has been done since then (3-10). These studies showed that the FRDA locus is most tightly linked to the two independently isolated loci D9S5 and D9S15 that lie only 250 kilobases (kb) apart. Very recently, however, rare recombination events were reported that appeared to exclude the gene from the region between D9S15 and the 26P marker at D9S5 (12, 13). One of these recombinants (13), as well as the analysis of FRDA-linked haplotypes in a population with a founder effect (14), suggested that the disease gene lies on the D9S5 side of the D9SJ5-D9S5 interval. Evolutionarily conserved seq...

Isolation and characterization of mammalian homologues of Caenorhabditis elegans lin-7: localization at cell-cell junctions

“…After the submission of this paper, the sequences of three mammalian lin-7 homologues were reported (Butz et al, 1998). These homologues were shown to make a ternary complex with CASK and X11/Mint in synapses (Duclos et al, 1993;Okamoto and Sudhof, 1997). The gene which had originally been reported as C. elegans lin-10 turned out to be incorrect, and the gene homologous to X11/Mint is now identi®ed to be an authentic C. elegans lin-10 ( Rongo et al, 1998).…”

Molecular cloning of a mouse epithelial protein‐tyrosine phosphatase with similarities to submembranous proteins

“…Most of these proteins contain a single DHR motif, such as LCF [Cruikshank et al, 1994], syntrophins [Adams et al, 1993b], AF-6 [Prasad et al, 1993], dishevelled [Theisen et al, 1994], X I1 [Duclos et al, 1993], and the product from an altered rosl transcript [Sharma et al, 1989]. Interestingly, lymphocyte chemoattractant factor (LCF) is a novel type of interleu kin that consists almost entirely of a single DHR motif and whose biological activity depends on autoaggregation [Cruikshank et al, 1994], sug gesting that DHR motifs mediate homophilic interactions.…”

“…The human XI1 pro tein contains two DHR motifs at its C-terminus. This protein is a candidate for Friedreich Ataxia (FRDA), an autosomal recessive degenerative disorder affecting both central and peripheral nervous systems [Duclos et al, 1993]. A crucial role for XI1 as part of the membrane skeleton in establishing polarity of neuronal cells would be in line with the observed FRDA phenotype.…”

Autoinhibition of X11/Mint scaffold proteins revealed by the closed conformation of the PDZ tandem

“…[1][2][3][4][5]. X11a/Mint1 and X11b/Mint2 are neuron-specific proteins, whereas X11g/Mint3 is ubiquitously expressed 2,[6][7][8][9] .…”