Identification of a novel, putative cataract-causing allele in CRYAA (G98R) in an Indian family

Sathiyavedu T. Santhiya, Torben Söker, Norman Klopp, Thomas Illig, M. V.S. Prakash, Bhavani Selvaraj, Puthiya M. Gopinath, Jochen Graw

Research output: Contribution to journalArticle

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Abstract

Purpose: The aim of the present study was to investigate the molecular basis underlying a nonsyndromic presenile autosomal dominant cataract in a three-generation pedigree. The phenotype was progressive from a peripheral ring-like opacity to a total cataract with advancing age from teenage to adulthood. The visual impairment started as problem in distant vision at the age of 16 years, to diminishing vision by the age of 24. Methods: Clinical interventions included complete ophthalmological examination, a collection of case history, and pedigree details. Blood samples were collected from available family members irrespective of their clinical status. A functional candidate gene approach was employed for PCR screening and sequencing of the exons and their flanking regions of CRYGC, CRYGD, and CRYAA genes. For structural consequences of the mutated αA-crystallin we used the bioinformatics tool of the ExPASy server. Results: Sequence analysis of CRYGC and CRYGD genes excluded possible causative mutations but identified known polymorphisms. Sequencing of the exons of the CRYAA gene identified a sequence variation in exon 2 (292 G->A) with a substitution of Gly to Arg at position 98. All three affected members revealed this change but it was not observed in the unaffected father or sister. The putative mutation obliterated a restriction site for the enzyme BstDSI. The same was checked in controls representing the general population of the same ethnicity (n = 30) and of randomly selected DNA samples from ophthalmologically normal individuals from the population-based KORA S4 study (n = 96). Moreover, the Gly at position 98 is highly conserved throughout the animal kingdom. For the mutant protein, the isoelectric point was raised from pH 5.77 to 5.96. Moreover, an extended α-helical structure is predicted in this region. Conclusions: The G98R mutation segregates only in affected family members and is not seen in representative controls. It represents very likely the fourth dominant cataract-causing allele in CRYAA. In all reported alleles the basic amino acid Arg is involved, suggesting the major importance of the net charge of the αA-crystallin for functional integrity in the lens.

Original languageEnglish
Pages (from-to)768-773
Number of pages6
JournalMolecular Vision
Volume12
Publication statusPublished - 12-07-2006
Externally publishedYes

Fingerprint

Cataract
Alleles
Exons
Crystallins
Pedigree
Mutation
Genes
Basic Amino Acids
Vision Disorders
Isoelectric Point
Mutant Proteins
Computational Biology
Fathers
Population
Lenses
Sequence Analysis
Siblings
Phenotype
Polymerase Chain Reaction
DNA

All Science Journal Classification (ASJC) codes

  • Ophthalmology

Cite this

Santhiya, S. T., Söker, T., Klopp, N., Illig, T., Prakash, M. V. S., Selvaraj, B., ... Graw, J. (2006). Identification of a novel, putative cataract-causing allele in CRYAA (G98R) in an Indian family. Molecular Vision, 12, 768-773.
Santhiya, Sathiyavedu T. ; Söker, Torben ; Klopp, Norman ; Illig, Thomas ; Prakash, M. V.S. ; Selvaraj, Bhavani ; Gopinath, Puthiya M. ; Graw, Jochen. / Identification of a novel, putative cataract-causing allele in CRYAA (G98R) in an Indian family. In: Molecular Vision. 2006 ; Vol. 12. pp. 768-773.
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abstract = "Purpose: The aim of the present study was to investigate the molecular basis underlying a nonsyndromic presenile autosomal dominant cataract in a three-generation pedigree. The phenotype was progressive from a peripheral ring-like opacity to a total cataract with advancing age from teenage to adulthood. The visual impairment started as problem in distant vision at the age of 16 years, to diminishing vision by the age of 24. Methods: Clinical interventions included complete ophthalmological examination, a collection of case history, and pedigree details. Blood samples were collected from available family members irrespective of their clinical status. A functional candidate gene approach was employed for PCR screening and sequencing of the exons and their flanking regions of CRYGC, CRYGD, and CRYAA genes. For structural consequences of the mutated αA-crystallin we used the bioinformatics tool of the ExPASy server. Results: Sequence analysis of CRYGC and CRYGD genes excluded possible causative mutations but identified known polymorphisms. Sequencing of the exons of the CRYAA gene identified a sequence variation in exon 2 (292 G->A) with a substitution of Gly to Arg at position 98. All three affected members revealed this change but it was not observed in the unaffected father or sister. The putative mutation obliterated a restriction site for the enzyme BstDSI. The same was checked in controls representing the general population of the same ethnicity (n = 30) and of randomly selected DNA samples from ophthalmologically normal individuals from the population-based KORA S4 study (n = 96). Moreover, the Gly at position 98 is highly conserved throughout the animal kingdom. For the mutant protein, the isoelectric point was raised from pH 5.77 to 5.96. Moreover, an extended α-helical structure is predicted in this region. Conclusions: The G98R mutation segregates only in affected family members and is not seen in representative controls. It represents very likely the fourth dominant cataract-causing allele in CRYAA. In all reported alleles the basic amino acid Arg is involved, suggesting the major importance of the net charge of the αA-crystallin for functional integrity in the lens.",
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Santhiya, ST, Söker, T, Klopp, N, Illig, T, Prakash, MVS, Selvaraj, B, Gopinath, PM & Graw, J 2006, 'Identification of a novel, putative cataract-causing allele in CRYAA (G98R) in an Indian family', Molecular Vision, vol. 12, pp. 768-773.

Identification of a novel, putative cataract-causing allele in CRYAA (G98R) in an Indian family. / Santhiya, Sathiyavedu T.; Söker, Torben; Klopp, Norman; Illig, Thomas; Prakash, M. V.S.; Selvaraj, Bhavani; Gopinath, Puthiya M.; Graw, Jochen.

In: Molecular Vision, Vol. 12, 12.07.2006, p. 768-773.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Identification of a novel, putative cataract-causing allele in CRYAA (G98R) in an Indian family

AU - Santhiya, Sathiyavedu T.

AU - Söker, Torben

AU - Klopp, Norman

AU - Illig, Thomas

AU - Prakash, M. V.S.

AU - Selvaraj, Bhavani

AU - Gopinath, Puthiya M.

AU - Graw, Jochen

PY - 2006/7/12

Y1 - 2006/7/12

N2 - Purpose: The aim of the present study was to investigate the molecular basis underlying a nonsyndromic presenile autosomal dominant cataract in a three-generation pedigree. The phenotype was progressive from a peripheral ring-like opacity to a total cataract with advancing age from teenage to adulthood. The visual impairment started as problem in distant vision at the age of 16 years, to diminishing vision by the age of 24. Methods: Clinical interventions included complete ophthalmological examination, a collection of case history, and pedigree details. Blood samples were collected from available family members irrespective of their clinical status. A functional candidate gene approach was employed for PCR screening and sequencing of the exons and their flanking regions of CRYGC, CRYGD, and CRYAA genes. For structural consequences of the mutated αA-crystallin we used the bioinformatics tool of the ExPASy server. Results: Sequence analysis of CRYGC and CRYGD genes excluded possible causative mutations but identified known polymorphisms. Sequencing of the exons of the CRYAA gene identified a sequence variation in exon 2 (292 G->A) with a substitution of Gly to Arg at position 98. All three affected members revealed this change but it was not observed in the unaffected father or sister. The putative mutation obliterated a restriction site for the enzyme BstDSI. The same was checked in controls representing the general population of the same ethnicity (n = 30) and of randomly selected DNA samples from ophthalmologically normal individuals from the population-based KORA S4 study (n = 96). Moreover, the Gly at position 98 is highly conserved throughout the animal kingdom. For the mutant protein, the isoelectric point was raised from pH 5.77 to 5.96. Moreover, an extended α-helical structure is predicted in this region. Conclusions: The G98R mutation segregates only in affected family members and is not seen in representative controls. It represents very likely the fourth dominant cataract-causing allele in CRYAA. In all reported alleles the basic amino acid Arg is involved, suggesting the major importance of the net charge of the αA-crystallin for functional integrity in the lens.

AB - Purpose: The aim of the present study was to investigate the molecular basis underlying a nonsyndromic presenile autosomal dominant cataract in a three-generation pedigree. The phenotype was progressive from a peripheral ring-like opacity to a total cataract with advancing age from teenage to adulthood. The visual impairment started as problem in distant vision at the age of 16 years, to diminishing vision by the age of 24. Methods: Clinical interventions included complete ophthalmological examination, a collection of case history, and pedigree details. Blood samples were collected from available family members irrespective of their clinical status. A functional candidate gene approach was employed for PCR screening and sequencing of the exons and their flanking regions of CRYGC, CRYGD, and CRYAA genes. For structural consequences of the mutated αA-crystallin we used the bioinformatics tool of the ExPASy server. Results: Sequence analysis of CRYGC and CRYGD genes excluded possible causative mutations but identified known polymorphisms. Sequencing of the exons of the CRYAA gene identified a sequence variation in exon 2 (292 G->A) with a substitution of Gly to Arg at position 98. All three affected members revealed this change but it was not observed in the unaffected father or sister. The putative mutation obliterated a restriction site for the enzyme BstDSI. The same was checked in controls representing the general population of the same ethnicity (n = 30) and of randomly selected DNA samples from ophthalmologically normal individuals from the population-based KORA S4 study (n = 96). Moreover, the Gly at position 98 is highly conserved throughout the animal kingdom. For the mutant protein, the isoelectric point was raised from pH 5.77 to 5.96. Moreover, an extended α-helical structure is predicted in this region. Conclusions: The G98R mutation segregates only in affected family members and is not seen in representative controls. It represents very likely the fourth dominant cataract-causing allele in CRYAA. In all reported alleles the basic amino acid Arg is involved, suggesting the major importance of the net charge of the αA-crystallin for functional integrity in the lens.

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Santhiya ST, Söker T, Klopp N, Illig T, Prakash MVS, Selvaraj B et al. Identification of a novel, putative cataract-causing allele in CRYAA (G98R) in an Indian family. Molecular Vision. 2006 Jul 12;12:768-773.