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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 chromatograms of causal mutations identified in PKCC001 and PKCC113.Sequence chromatograms of A) Unaffected individual 15 homozygous for wild-type allele; B) unaffected individual 17 heterozygous and C) affected individual 19, homozygous for c.34C>T (p.R12C). Sequence chromatograms of D) unaffected individual 6 homozygous for wild-type allele, E) unaffected individual 8 heterozygous and F) affected individual 10 homozygous for c.31C>T (p.R11C). The arrows point to c.31C and c.34C of CRYAB mutated in PKCC113 and PKCC001, respectively. It is worth to note that mutations identified in PKCC001 and PKCC113 are adjacent amino acids i.e. Arg11, and Arg12.
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pone.0137973.g003: Sequence chromatograms of causal mutations identified in PKCC001 and PKCC113.Sequence chromatograms of A) Unaffected individual 15 homozygous for wild-type allele; B) unaffected individual 17 heterozygous and C) affected individual 19, homozygous for c.34C>T (p.R12C). Sequence chromatograms of D) unaffected individual 6 homozygous for wild-type allele, E) unaffected individual 8 heterozygous and F) affected individual 10 homozygous for c.31C>T (p.R11C). The arrows point to c.31C and c.34C of CRYAB mutated in PKCC113 and PKCC001, respectively. It is worth to note that mutations identified in PKCC001 and PKCC113 are adjacent amino acids i.e. Arg11, and Arg12.

Mentions: This region harbors CRYAB, a gene previously associated with cardiomyopathy and congenital cataracts. Bi-directional sequencing of CRYAB identified a missense variation: c.34C>T; p.R12C that segregated with the disease phenotype in PKCC001 (Figs 1A and 3A–3C). The exome variant server analysis identified the variant in heterozygous form (AA = 0/AG = 1/GG = 4295) in one individual representing a minor allele frequency (MAF) of 0.0116 in European American population. Likewise, dbSNP analysis revealed MAF score of 0.0010 for rs375933774 (c.34C>T) based on 1000 Genomes database. This variation was not found in 384 control chromosomes of Pakistani and 48 control chromosomes of Saudi decent. A two-point LOD score of 5.53 at θ = 0 was obtained for the causal variant (Table 1A).


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 chromatograms of causal mutations identified in PKCC001 and PKCC113.Sequence chromatograms of A) Unaffected individual 15 homozygous for wild-type allele; B) unaffected individual 17 heterozygous and C) affected individual 19, homozygous for c.34C>T (p.R12C). Sequence chromatograms of D) unaffected individual 6 homozygous for wild-type allele, E) unaffected individual 8 heterozygous and F) affected individual 10 homozygous for c.31C>T (p.R11C). The arrows point to c.31C and c.34C of CRYAB mutated in PKCC113 and PKCC001, respectively. It is worth to note that mutations identified in PKCC001 and PKCC113 are adjacent amino acids i.e. Arg11, and Arg12.
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC4581838&req=5

pone.0137973.g003: Sequence chromatograms of causal mutations identified in PKCC001 and PKCC113.Sequence chromatograms of A) Unaffected individual 15 homozygous for wild-type allele; B) unaffected individual 17 heterozygous and C) affected individual 19, homozygous for c.34C>T (p.R12C). Sequence chromatograms of D) unaffected individual 6 homozygous for wild-type allele, E) unaffected individual 8 heterozygous and F) affected individual 10 homozygous for c.31C>T (p.R11C). The arrows point to c.31C and c.34C of CRYAB mutated in PKCC113 and PKCC001, respectively. It is worth to note that mutations identified in PKCC001 and PKCC113 are adjacent amino acids i.e. Arg11, and Arg12.
Mentions: This region harbors CRYAB, a gene previously associated with cardiomyopathy and congenital cataracts. Bi-directional sequencing of CRYAB identified a missense variation: c.34C>T; p.R12C that segregated with the disease phenotype in PKCC001 (Figs 1A and 3A–3C). The exome variant server analysis identified the variant in heterozygous form (AA = 0/AG = 1/GG = 4295) in one individual representing a minor allele frequency (MAF) of 0.0116 in European American population. Likewise, dbSNP analysis revealed MAF score of 0.0010 for rs375933774 (c.34C>T) based on 1000 Genomes database. This variation was not found in 384 control chromosomes of Pakistani and 48 control chromosomes of Saudi decent. A two-point LOD score of 5.53 at θ = 0 was obtained for the causal variant (Table 1A).

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