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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

Slit lamp photographs of individual 19 of family PKCC001 illustrating nuclear cataracts.
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pone.0137973.g002: Slit lamp photographs of individual 19 of family PKCC001 illustrating nuclear cataracts.

Mentions: An inbred large multigenerational family, PKCC001 with multiple individuals having congenital cataracts was recruited from the Punjab province of Pakistan to investigate the genetic basis of congenital cataracts (Fig 1A). A detailed medical history was obtained by interviewing all participating members, which ruled out any systemic abnormalities and/or extraocular phenotypes. According to the family elders, development of cataracts in affected individuals was first observed within a year after birth suggesting an early, perhaps a congenital onset. All affected individuals except individual 19 of family PKCC001 had been operated on to remove the cataractous lens prior to enrollment in the study and, therefore, we were unable to document their phenotype. An ophthalmic examination performed using a slit lamp microscopy revealed nuclear cataracts in individual 19 (Fig 2).


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)

Slit lamp photographs of individual 19 of family PKCC001 illustrating nuclear cataracts.
© Copyright Policy
Related In: Results  -  Collection

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

pone.0137973.g002: Slit lamp photographs of individual 19 of family PKCC001 illustrating nuclear cataracts.
Mentions: An inbred large multigenerational family, PKCC001 with multiple individuals having congenital cataracts was recruited from the Punjab province of Pakistan to investigate the genetic basis of congenital cataracts (Fig 1A). A detailed medical history was obtained by interviewing all participating members, which ruled out any systemic abnormalities and/or extraocular phenotypes. According to the family elders, development of cataracts in affected individuals was first observed within a year after birth suggesting an early, perhaps a congenital onset. All affected individuals except individual 19 of family PKCC001 had been operated on to remove the cataractous lens prior to enrollment in the study and, therefore, we were unable to document their phenotype. An ophthalmic examination performed using a slit lamp microscopy revealed nuclear cataracts in individual 19 (Fig 2).

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