title: Mutations in TULP1, NR2E3, and MFRP genes in Indian families with autosomal recessive retinitis pigmentosa.
abstract: OBJECTIVE
  To identify genes underlying autosomal recessive retinitis pigmentosa (ARRP) by homozygosity mapping.
  
  
  METHODS
  Families with ARRP were recruited after complete ophthalmic evaluation of all members and diagnosis of RP by predefined criteria. Genomic DNA from affected members of 26 families was genotyped on Illumina single nucleotide polymorphism (SNP) 6.0 K arrays with standard procedures. Genotypes were evaluated for homozygous regions that were common and concordant between affected members of each family. The genes mapping to homozygous intervals within these families were screened for pathogenic changes with PCR amplification and sequencing of coding regions. Co-segegration of sequence changes with disease was determined within each pedigree, and each variation was tested for presence in 100 unrelated normal controls.
  
  
  RESULTS
  A genome-wide scan for homozygosity showed homozygous regions harboring the tubby like protein 1 gene (TULP1; chromosome 6) in one family, the nuclear receptor subfamily 2, group E, member 3 gene (NR2E3; chromosome 15) in three families, and the membrane frizzled-related protein gene (MFRP; chromosome 11) in one family. Screening of the three genes in the respective families revealed homozygous disease-causing mutations in three families. These included a missense mutation in TULP1, a deletion-cum-insertion in NR2E3, and a single base deletion in MFRP. Patients from all three families had a rod-cone type of dystrophy with night blindness initially. The NR2E3 and MFRP genes were associated with fundus features atypical of RP.
  
  
  CONCLUSIONS
  This study shows involvement of the TULP1, NR2E3, and MFRP genes in ARRP in Indian cases. Genome-wide screening with SNP arrays followed by a prioritized candidate gene evaluation is useful in identifying genes in these patients.
authors.affiliation: Kallam Anji Reddy Molecular Genetics Laboratory, Hyderabad Eye Research Foundation, Hyderabad, Andhra Pradesh, India. chitra@lvpei.org
authors.forename: Chitra
authors.initials: C
authors.lastname: Kannabiran
authors.forename: Hardeep
authors.initials: H
authors.lastname: Singh
authors.forename: Nishika
authors.initials: N
authors.lastname: Sahini
authors.forename: Subhadra
authors.initials: S
authors.lastname: Jalali
authors.forename: Gayathri
authors.initials: G
authors.lastname: Mohan
mesh_terms: D000293:Adolescent; D000328:Adult; D000595:Amino Acid Sequence; D001483:Base Sequence; D016022:Case-Control Studies; D002648:Child; D003241:Consanguinity; D005136:Eye Proteins / Q000235:genetics*; D005260:Female; D005808:Genes, Recessive; D006720:Homozygote; D006801:Humans; D007194:India; D008297:Male; D008565:Membrane Proteins / Q000235:genetics*; D008969:Molecular Sequence Data; D009154:Mutation / Q000235:genetics*; D020411:Oligonucleotide Array Sequence Analysis; D057093:Orphan Nuclear Receptors / Q000235:genetics*; D010375:Pedigree; D012174:Retinitis Pigmentosa / Q000235:genetics*; D000099274:Frizzled-Related Proteins
chemical_list: D005136:Eye Proteins; D008565:Membrane Proteins; D057093:Orphan Nuclear Receptors; C490110:MFRP protein, human; D000099274:Frizzled-Related Proteins; C403073:NR2E3 protein, human; C105443:TULP1 protein, human