L. Montermini et al., THE FRIEDREICH ATAXIA CRITICAL REGION SPANS A 150-KB INTERVAL ON CHROMOSOME 9Q13, American journal of human genetics, 57(5), 1995, pp. 1061-1067
By analysis of crossovers in key recombinant families and by homozygos
ity analysis of inbred families, the Friedreich ataxia (FRDA) locus wa
s localized in a 300-kb interval between the X104 gene and the microsa
tellite marker FR8 (D9S888). By homology searches of the sequence data
bases, we identified X104 as the human tight junction protein ZO-2 gen
e. We generated a large-scale physical map of the FRDA region by pulse
d-held gel electrophoresis analysis of genomic DNA and of three YAC cl
ones derived from different libraries, and we constructed an uninterru
pted cosmid contig spanning the FRDA locus. The cAMP-dependent protein
kinase gamma-catalytic subunit gene was identified within the critica
l FRDA interval, but it was excluded as candidate because of its biolo
gical properties and because of lack of mutations in FRDA patients. Si
x new polymorphic markers were isolated between FR2 (D9S886) and FR8 (
D9S888), which were used for homozygosity analysis in a family in whic
h parents of an affected child are distantly related. An ancient recom
bination involving the centromeric FRDA flanking markers had been prev
iously demonstrated in this family. Homozygosity analysis indicated th
at the FRDA gene is localized in the telomeric 150 kb of the FR2-FR8 i
nterval.