Identification of candidate regions for a novel Usher syndrome type II locus.
OBJECTIVE
Chronic diseases affecting the inner ear and the retina cause severe impairments to our communication systems. In more than half of the cases, Usher syndrome (USH) is the origin of these double defects. Patients with USH type II (USH2) have retinitis pigmentosa (RP) that develops during puberty, moderate to severe hearing impairment with downsloping pure-tone audiogram, and normal vestibular function. Four loci and three genes are known for USH2. In this study, we proposed to localize the gene responsible for USH2 in a consanguineous family of Tunisian origin.


METHODS
Affected members underwent detailed ocular and audiologic characterization. One Tunisian family with USH2 and 45 healthy controls unrelated to the family were recruited. Two affected and six unaffected family members attended our study. DNA samples of eight family members were genotyped with polymorphic markers. Two-point and multipoint LOD scores were calculated using Genehunter software v2.1. Sequencing was used to investigate candidate genes.


RESULTS
Haplotype analysis showed no significant linkage to any known USH gene or locus. A genome-wide screen, using microsatellite markers, was performed, allowing the identification of three homozygous regions in chromosomes 2, 4, and 15. We further confirmed and refined these three regions using microsatellite and single-nucleotide polymorphisms. With recessive mode of inheritance, the highest multipoint LOD score of 1.765 was identified for the candidate regions on chromosomes 4 and 15. The chromosome 15 locus is large (55 Mb), underscoring the limited number of meioses in the consanguineous pedigree. Moreover, the linked, homozygous chromosome 15q alleles, unlike those of the chromosome 2 and 4 loci, are infrequent in the local population. Thus, the data strongly suggest that the novel locus for USH2 is likely to reside on 15q.


CONCLUSIONS
Our data provide a basis for the localization and the identification of a novel gene implicated in USH2, most likely localized on 15q.
Ben Rebeh
Imen
I
Unité Cibles pour le Diagnostic et la Thérapie, Centre de Biotechnologie de Sfax, Tunisie
Benzina
Zeineb
Z
Dhouib
Houria
H
Hadjamor
Imen
I
Amyere
Mustapha
M
Ayadi
Leila
L
Turki
Khalil
K
Hammami
Bouthaina
B
Kmiha
Noureddine
N
Kammoun
Hassen
H
Hakim
Bochra
B
Charfedine
Ilhem
I
Vikkula
Miikka
M
Ghorbel
Abdelmonem
A
Ayadi
Hammadi
H
Masmoudi
Saber
S
D000293:Adolescent; D000328:Adult; D000368:Aged; D020090:Chromosome Segregation; D004596:Electroretinography; D005190:Family; D005260:Female; D005820:Genetic Testing; D015894:Genome, Human / Q000235:genetics; D006239:Haplotypes; D006319:Hearing Loss, Sensorineural / Q000235:genetics; D006720:Homozygote; D006801:Humans; D008126:Lod Score; D008297:Male; D018895:Microsatellite Repeats / Q000235:genetics; D008875:Middle Aged; D010375:Pedigree; D014416:Tunisia; D052245:Usher Syndromes / Q000235:genetics* / Q000503:physiopathology; D014794:Visual Fields