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Missense Mutations in CRYAB Are Liable for Recessive Congenital Cataracts.

Jiaox X, Khan SY, Irum B, Khan AO, Wang Q, Kabir F, Khan AA, Husnain T, Akram J, Riazuddin S, Hejtmancik JF, Riazuddin SA - PLoS ONE (2015)

Bottom Line: Subsequent interrogation of our entire cohort of familial cases identified a second familial case localized to chromosome 11q23 harboring a c.31C>T (p.R11C) mutation.Real-time PCR analysis identified the expression of Cryab in mouse lens as early as embryonic day 15 (E15) that increased significantly until postnatal day 6 (P6) with steady level of expression thereafter.Here, we report two novel missense mutations, p.R11C and p.R12C, in CRYAB associated with autosomal recessive congenital nuclear cataracts.

View Article: PubMed Central - PubMed

Affiliation: Ophthalmic Genetics and Visual Function Branch, National Eye Institute, National Institutes of Health, Bethesda, MD, 20892, United States of America.

ABSTRACT

Purpose: This study was initiated to identify causal mutations responsible for autosomal recessive congenital cataracts in consanguineous familial cases.

Methods: Affected individuals underwent a detailed ophthalmological and clinical examination, and slit-lamp photographs were ascertained for affected individuals who have not yet been operated for the removal of the cataractous lens. Blood samples were obtained, and genomic DNA was extracted from white blood cells. A genome-wide scan was completed with short tandem repeat (STR) markers, and the logarithm of odds (LOD) scores were calculated. Protein coding exons of CRYAB were sequenced, bi-directionally. Evolutionary conservation was investigated by aligning CRYAB orthologues, and the expression of Cryab in embryonic and postnatal mice lens was investigated with TaqMan probe.

Results: The clinical and ophthalmological examinations suggested that all affected individuals had nuclear cataracts. Genome-wide linkage analysis suggested a potential region on chromosome 11q23 harboring CRYAB. DNA sequencing identified a missense variation: c.34C>T (p.R12C) in CRYAB that segregated with the disease phenotype in the family. Subsequent interrogation of our entire cohort of familial cases identified a second familial case localized to chromosome 11q23 harboring a c.31C>T (p.R11C) mutation. In silico analyses suggested that the mutations identified in familial cases, p.R11C and p.R12C will not be tolerated by the three-dimensional structure of CRYAB. Real-time PCR analysis identified the expression of Cryab in mouse lens as early as embryonic day 15 (E15) that increased significantly until postnatal day 6 (P6) with steady level of expression thereafter.

Conclusion: Here, we report two novel missense mutations, p.R11C and p.R12C, in CRYAB associated with autosomal recessive congenital nuclear cataracts.

No MeSH data available.


Related in: MedlinePlus

Sequence alignment of CRYAB in mammalian orthologues illustrating the conservation of Arginine at positions 11 and 12.Primates, Euarchontoglires, Laurasiatheria, and Afrotheria are colored brown, green, purple and orange, respectively.
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pone.0137973.g004: Sequence alignment of CRYAB in mammalian orthologues illustrating the conservation of Arginine at positions 11 and 12.Primates, Euarchontoglires, Laurasiatheria, and Afrotheria are colored brown, green, purple and orange, respectively.

Mentions: We used SIFT and PolyPhen2 algorithms to evaluate the possible impact of p.R11C and p.R12C mutations on CRYAB. SIFT predictions suggested that both the R11C and R12C substitutions will not be tolerated by the native three-dimensional structure of CRYAB. The effect protein function score for R11C and R12C were 0.00 and 0.00, respectively (amino acids with probabilities < .05 are predicted to be deleterious). Likewise, Polyphen2 suggested that both the R11C and R12C substitutions are probably damaging to the CRYAB structure with a score of 1.00, and 1.00, respectively. We found that both arginines at position 11, and 12 are not only conserved in CRYAB mammalian orthologues (Fig 4) but also conserved in CRYAB vertebrate orthologues according to the UCSC genome browser (data not shown).


Missense Mutations in CRYAB Are Liable for Recessive Congenital Cataracts.

Jiaox X, Khan SY, Irum B, Khan AO, Wang Q, Kabir F, Khan AA, Husnain T, Akram J, Riazuddin S, Hejtmancik JF, Riazuddin SA - PLoS ONE (2015)

Sequence alignment of CRYAB in mammalian orthologues illustrating the conservation of Arginine at positions 11 and 12.Primates, Euarchontoglires, Laurasiatheria, and Afrotheria are colored brown, green, purple and orange, respectively.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4581838&req=5

pone.0137973.g004: Sequence alignment of CRYAB in mammalian orthologues illustrating the conservation of Arginine at positions 11 and 12.Primates, Euarchontoglires, Laurasiatheria, and Afrotheria are colored brown, green, purple and orange, respectively.
Mentions: We used SIFT and PolyPhen2 algorithms to evaluate the possible impact of p.R11C and p.R12C mutations on CRYAB. SIFT predictions suggested that both the R11C and R12C substitutions will not be tolerated by the native three-dimensional structure of CRYAB. The effect protein function score for R11C and R12C were 0.00 and 0.00, respectively (amino acids with probabilities < .05 are predicted to be deleterious). Likewise, Polyphen2 suggested that both the R11C and R12C substitutions are probably damaging to the CRYAB structure with a score of 1.00, and 1.00, respectively. We found that both arginines at position 11, and 12 are not only conserved in CRYAB mammalian orthologues (Fig 4) but also conserved in CRYAB vertebrate orthologues according to the UCSC genome browser (data not shown).

Bottom Line: Subsequent interrogation of our entire cohort of familial cases identified a second familial case localized to chromosome 11q23 harboring a c.31C>T (p.R11C) mutation.Real-time PCR analysis identified the expression of Cryab in mouse lens as early as embryonic day 15 (E15) that increased significantly until postnatal day 6 (P6) with steady level of expression thereafter.Here, we report two novel missense mutations, p.R11C and p.R12C, in CRYAB associated with autosomal recessive congenital nuclear cataracts.

View Article: PubMed Central - PubMed

Affiliation: Ophthalmic Genetics and Visual Function Branch, National Eye Institute, National Institutes of Health, Bethesda, MD, 20892, United States of America.

ABSTRACT

Purpose: This study was initiated to identify causal mutations responsible for autosomal recessive congenital cataracts in consanguineous familial cases.

Methods: Affected individuals underwent a detailed ophthalmological and clinical examination, and slit-lamp photographs were ascertained for affected individuals who have not yet been operated for the removal of the cataractous lens. Blood samples were obtained, and genomic DNA was extracted from white blood cells. A genome-wide scan was completed with short tandem repeat (STR) markers, and the logarithm of odds (LOD) scores were calculated. Protein coding exons of CRYAB were sequenced, bi-directionally. Evolutionary conservation was investigated by aligning CRYAB orthologues, and the expression of Cryab in embryonic and postnatal mice lens was investigated with TaqMan probe.

Results: The clinical and ophthalmological examinations suggested that all affected individuals had nuclear cataracts. Genome-wide linkage analysis suggested a potential region on chromosome 11q23 harboring CRYAB. DNA sequencing identified a missense variation: c.34C>T (p.R12C) in CRYAB that segregated with the disease phenotype in the family. Subsequent interrogation of our entire cohort of familial cases identified a second familial case localized to chromosome 11q23 harboring a c.31C>T (p.R11C) mutation. In silico analyses suggested that the mutations identified in familial cases, p.R11C and p.R12C will not be tolerated by the three-dimensional structure of CRYAB. Real-time PCR analysis identified the expression of Cryab in mouse lens as early as embryonic day 15 (E15) that increased significantly until postnatal day 6 (P6) with steady level of expression thereafter.

Conclusion: Here, we report two novel missense mutations, p.R11C and p.R12C, in CRYAB associated with autosomal recessive congenital nuclear cataracts.

No MeSH data available.


Related in: MedlinePlus