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Mutations in TULP1, NR2E3, and MFRP genes in Indian families with autosomal recessive retinitis pigmentosa.

Kannabiran C, Singh H, Sahini N, Jalali S, Mohan G - Mol. Vis. (2012)

Bottom Line: The NR2E3 and MFRP genes were associated with fundus features atypical of RP.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.

View Article: PubMed Central - PubMed

Affiliation: Kallam Anji Reddy Molecular Genetics Laboratory, Hyderabad Eye Research Foundation, Hyderabad, Andhra Pradesh, India. chitra@lvpei.org

ABSTRACT

Purpose: 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.

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Related in: MedlinePlus

Molecular and clinical details of patient from Family C with a mutation in the MFRP gene. A: The family pedigree is shown. B: Sequence of MFRP gene in normal control (top panel) and in patient C-1 (bottom panel). The arrows in the top and bottom panels respectively, mark the SNP c.492C>T (rs36015759) and the position of the single base deletion in patient C-1. C: Fundus montage of the right eye of patient C-1 (aged 21 years) from Family C with an MFRP gene mutation showing perifoveal pigment deposits, relative parafoveal sparing, diffuse extensive graying of retina with white flecks extending from arcades to the peripheral retina, and the presence of a peripheral reticular, bone corpuscular type of pigmentary retinopathy. There is not much disc pallor or arterial narrowing.
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f3: Molecular and clinical details of patient from Family C with a mutation in the MFRP gene. A: The family pedigree is shown. B: Sequence of MFRP gene in normal control (top panel) and in patient C-1 (bottom panel). The arrows in the top and bottom panels respectively, mark the SNP c.492C>T (rs36015759) and the position of the single base deletion in patient C-1. C: Fundus montage of the right eye of patient C-1 (aged 21 years) from Family C with an MFRP gene mutation showing perifoveal pigment deposits, relative parafoveal sparing, diffuse extensive graying of retina with white flecks extending from arcades to the peripheral retina, and the presence of a peripheral reticular, bone corpuscular type of pigmentary retinopathy. There is not much disc pallor or arterial narrowing.

Mentions: This gene was screened in Family C (Figure 3A) due to the presence of an 8.5 Mb homozygous region on chromosome 11 that included the MFRP gene locus. All three affected had a single base deletion in exon 5, c.498delC, at codon 166 of the protein (Pro166ProfsX26; NM_031433.2; Figure 3B). The parents were heterozygous carriers. Screening of 100 unrelated normal controls showed this change was absent in the control population. The frameshift resulting from this deletion leads to termination after 25 residues.


Mutations in TULP1, NR2E3, and MFRP genes in Indian families with autosomal recessive retinitis pigmentosa.

Kannabiran C, Singh H, Sahini N, Jalali S, Mohan G - Mol. Vis. (2012)

Molecular and clinical details of patient from Family C with a mutation in the MFRP gene. A: The family pedigree is shown. B: Sequence of MFRP gene in normal control (top panel) and in patient C-1 (bottom panel). The arrows in the top and bottom panels respectively, mark the SNP c.492C>T (rs36015759) and the position of the single base deletion in patient C-1. C: Fundus montage of the right eye of patient C-1 (aged 21 years) from Family C with an MFRP gene mutation showing perifoveal pigment deposits, relative parafoveal sparing, diffuse extensive graying of retina with white flecks extending from arcades to the peripheral retina, and the presence of a peripheral reticular, bone corpuscular type of pigmentary retinopathy. There is not much disc pallor or arterial narrowing.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3351411&req=5

f3: Molecular and clinical details of patient from Family C with a mutation in the MFRP gene. A: The family pedigree is shown. B: Sequence of MFRP gene in normal control (top panel) and in patient C-1 (bottom panel). The arrows in the top and bottom panels respectively, mark the SNP c.492C>T (rs36015759) and the position of the single base deletion in patient C-1. C: Fundus montage of the right eye of patient C-1 (aged 21 years) from Family C with an MFRP gene mutation showing perifoveal pigment deposits, relative parafoveal sparing, diffuse extensive graying of retina with white flecks extending from arcades to the peripheral retina, and the presence of a peripheral reticular, bone corpuscular type of pigmentary retinopathy. There is not much disc pallor or arterial narrowing.
Mentions: This gene was screened in Family C (Figure 3A) due to the presence of an 8.5 Mb homozygous region on chromosome 11 that included the MFRP gene locus. All three affected had a single base deletion in exon 5, c.498delC, at codon 166 of the protein (Pro166ProfsX26; NM_031433.2; Figure 3B). The parents were heterozygous carriers. Screening of 100 unrelated normal controls showed this change was absent in the control population. The frameshift resulting from this deletion leads to termination after 25 residues.

Bottom Line: The NR2E3 and MFRP genes were associated with fundus features atypical of RP.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.

View Article: PubMed Central - PubMed

Affiliation: Kallam Anji Reddy Molecular Genetics Laboratory, Hyderabad Eye Research Foundation, Hyderabad, Andhra Pradesh, India. chitra@lvpei.org

ABSTRACT

Purpose: 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.

Show MeSH
Related in: MedlinePlus