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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

Details of ARRP patient from Family A with a mutation in the TULP1 gene. A: Pedigree shows affected (dark symbols) and unaffected (open) symbols, with squares representing men and circles representing women. A double line connecting spouses denotes consanguinity. B: Sequence chromatogram of the TULP1 gene in normal control (top) and in patient A-1 (bottom) with homozygous mutation T>G (arrows), resulting in a codon change AAT (Asn) to AAG (Lys). The protein sequence alignment of TULP1 from different species (C) shows conservation of the Asn349 residue. Fundus photograph of right (D) and left (E) eyes of patient A-1 taken at age nine years shows greyish discoloration of the retina due to widespread RPE atrophy, severe arterial narrowing, disc pallor, and cellophane retinopathy due to a thin epiretinal membrane.
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f1: Details of ARRP patient from Family A with a mutation in the TULP1 gene. A: Pedigree shows affected (dark symbols) and unaffected (open) symbols, with squares representing men and circles representing women. A double line connecting spouses denotes consanguinity. B: Sequence chromatogram of the TULP1 gene in normal control (top) and in patient A-1 (bottom) with homozygous mutation T>G (arrows), resulting in a codon change AAT (Asn) to AAG (Lys). The protein sequence alignment of TULP1 from different species (C) shows conservation of the Asn349 residue. Fundus photograph of right (D) and left (E) eyes of patient A-1 taken at age nine years shows greyish discoloration of the retina due to widespread RPE atrophy, severe arterial narrowing, disc pallor, and cellophane retinopathy due to a thin epiretinal membrane.

Mentions: The TULP1 gene was screened in Family A (Figure 1A) due to the presence of homozygosity at this locus extending to 8.1 Mb. A homozygous missense change c.1047T>G (NM_003322.3) was detected in two affected individuals, corresponding to Asn349Lys (Figure 1B). A blood sample was not collected from one of the affected individuals as the patient was mentally challenged. The unaffected parents were carriers of the mutation. This mutation was not found in 100 unrelated normal controls. The Asn349 residue is located in the conserved C-terminal tubby domain. Multiple sequence alignment of the protein shows that this residue is highly conserved (Figure 1C). Analysis of the substitution with the SIFT and PolyPhen tools predicted that the change is probably damaging to the protein.


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)

Details of ARRP patient from Family A with a mutation in the TULP1 gene. A: Pedigree shows affected (dark symbols) and unaffected (open) symbols, with squares representing men and circles representing women. A double line connecting spouses denotes consanguinity. B: Sequence chromatogram of the TULP1 gene in normal control (top) and in patient A-1 (bottom) with homozygous mutation T>G (arrows), resulting in a codon change AAT (Asn) to AAG (Lys). The protein sequence alignment of TULP1 from different species (C) shows conservation of the Asn349 residue. Fundus photograph of right (D) and left (E) eyes of patient A-1 taken at age nine years shows greyish discoloration of the retina due to widespread RPE atrophy, severe arterial narrowing, disc pallor, and cellophane retinopathy due to a thin epiretinal membrane.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

f1: Details of ARRP patient from Family A with a mutation in the TULP1 gene. A: Pedigree shows affected (dark symbols) and unaffected (open) symbols, with squares representing men and circles representing women. A double line connecting spouses denotes consanguinity. B: Sequence chromatogram of the TULP1 gene in normal control (top) and in patient A-1 (bottom) with homozygous mutation T>G (arrows), resulting in a codon change AAT (Asn) to AAG (Lys). The protein sequence alignment of TULP1 from different species (C) shows conservation of the Asn349 residue. Fundus photograph of right (D) and left (E) eyes of patient A-1 taken at age nine years shows greyish discoloration of the retina due to widespread RPE atrophy, severe arterial narrowing, disc pallor, and cellophane retinopathy due to a thin epiretinal membrane.
Mentions: The TULP1 gene was screened in Family A (Figure 1A) due to the presence of homozygosity at this locus extending to 8.1 Mb. A homozygous missense change c.1047T>G (NM_003322.3) was detected in two affected individuals, corresponding to Asn349Lys (Figure 1B). A blood sample was not collected from one of the affected individuals as the patient was mentally challenged. The unaffected parents were carriers of the mutation. This mutation was not found in 100 unrelated normal controls. The Asn349 residue is located in the conserved C-terminal tubby domain. Multiple sequence alignment of the protein shows that this residue is highly conserved (Figure 1C). Analysis of the substitution with the SIFT and PolyPhen tools predicted that the change is probably damaging to the protein.

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