Identification of recurrent and novel mutations in TULP1 in Pakistani families with early-onset retinitis pigmentosa.
OBJECTIVE
To identify the genetic defects underlying retinitis pigmentosa (RP) in Pakistani families.


METHODS
Genome-wide high-density single-nucleotide-polymorphism microarray analysis was performed using the DNA of nine affected individuals from two large families with multiple consanguineous marriages. Data were analyzed to identify homozygous regions that are shared by affected sibs in each family. Sanger sequencing was performed for genes previously implicated in autosomal recessive RP and allied retinal dystrophies that resided in the identified homozygous regions. Probands from both families underwent fundus examination and electroretinogram measurements.


RESULTS
The tubby-like protein 1 gene (TULP1) was present in the largest homozygous region in both families. Sequence analysis identified a previously reported mutation (c.1138A>G; p.Thr380Ala) in one family and a novel pathogenic variant (c.1445G>A; p.Arg482Gln) in the other family. Both variants were found to be present in a homozygous state in all affected individuals, were heterozygous present in the unaffected parents, and heterozygous present or absent in normal individuals. Affected individuals of both families showed an early-onset form of RP.


CONCLUSIONS
Homozygosity mapping, combined with candidate-gene analysis, successfully identified genetic defects in TULP1 in two large Pakistani families with early-onset retinitis pigmentosa.
Department of Biosciences, Faculty of Science, COMSATS Institute of Information Technology, Islamabad, Pakistan.
Muhammad
M
Ajmal
Muhammad Imran
MI
Khan
Shazia
S
Micheal
Waqas
W
Ahmed
Ashfa
A
Shah
Hanka
H
Venselaar
Habib
H
Bokhari
Aisha
A
Azam
Nadia Khalida
NK
Waheed
Rob W J
RW
Collin
Anneke I
AI
den Hollander
Raheel
R
Qamar
Frans P M
FP
Cremers
D000328:Adult; D017668:Age of Onset; D001483:Base Sequence; D002675:Child, Preschool; D003241:Consanguinity; D004596:Electroretinography; D005136:Eye Proteins / Q000235:genetics*; D005260:Female; D005808:Genes, Recessive; D008040:Genetic Linkage; D005838:Genotype; D006720:Homozygote; D006801:Humans; D008297:Male; D018895:Microsatellite Repeats; D008969:Molecular Sequence Data; D009154:Mutation; D020411:Oligonucleotide Array Sequence Analysis; D010154:Pakistan; D010375:Pedigree; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D012174:Retinitis Pigmentosa / Q000235:genetics* / Q000473:pathology
D005136:Eye Proteins; C105443:TULP1 protein, human