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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

Expression profile of alpha-crystallin in developing mouse lens.The expression of Cryaa (blue) and Cryab (orange) at different developmental time points was normalized to Gapdh. A logarithmic trend line (red) fits the Cryab expression with an R2 value of 0.7742. The x-axis and y-axis represent developmental time points and normalized expression of each mRNA, respectively.
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pone.0137973.g006: Expression profile of alpha-crystallin in developing mouse lens.The expression of Cryaa (blue) and Cryab (orange) at different developmental time points was normalized to Gapdh. A logarithmic trend line (red) fits the Cryab expression with an R2 value of 0.7742. The x-axis and y-axis represent developmental time points and normalized expression of each mRNA, respectively.

Mentions: Dubin and colleagues, previously reported the expression of CRYAB in multiple tissues including the ocular lens [22]. We investigated the expression of both Cryaa and Cryab in embryonic and postnatal murine lens. As shown in Fig 6, we observed expression of both α-Crystallins in mouse lens as early as embryonic day 15 (E15); nonetheless, the level of Cryaa expression was an order of magnitude higher compared with expression of Cryab. In sharp contrast to Cryaa of which the expression levels remain nearly steady over the 12 developmental stages investigated here, the expression level of Cryab mimics a logarithmic pattern in early stages of increasing significantly up until postnatal day 6 (P6) and from there onwards the expression level remains steady over the remaining time course until two months of age (Fig 6).


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)

Expression profile of alpha-crystallin in developing mouse lens.The expression of Cryaa (blue) and Cryab (orange) at different developmental time points was normalized to Gapdh. A logarithmic trend line (red) fits the Cryab expression with an R2 value of 0.7742. The x-axis and y-axis represent developmental time points and normalized expression of each mRNA, respectively.
© Copyright Policy
Related In: Results  -  Collection

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

pone.0137973.g006: Expression profile of alpha-crystallin in developing mouse lens.The expression of Cryaa (blue) and Cryab (orange) at different developmental time points was normalized to Gapdh. A logarithmic trend line (red) fits the Cryab expression with an R2 value of 0.7742. The x-axis and y-axis represent developmental time points and normalized expression of each mRNA, respectively.
Mentions: Dubin and colleagues, previously reported the expression of CRYAB in multiple tissues including the ocular lens [22]. We investigated the expression of both Cryaa and Cryab in embryonic and postnatal murine lens. As shown in Fig 6, we observed expression of both α-Crystallins in mouse lens as early as embryonic day 15 (E15); nonetheless, the level of Cryaa expression was an order of magnitude higher compared with expression of Cryab. In sharp contrast to Cryaa of which the expression levels remain nearly steady over the 12 developmental stages investigated here, the expression level of Cryab mimics a logarithmic pattern in early stages of increasing significantly up until postnatal day 6 (P6) and from there onwards the expression level remains steady over the remaining time course until two months of age (Fig 6).

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