title: Missense Mutations in CRYAB Are Liable for Recessive Congenital Cataracts.
abstract: This study was initiated to identify causal mutations responsible for autosomal recessive congenital cataracts in consanguineous familial cases.
  
  
  
  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.
  
  
  
  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.
  
  
  
  Here, we report two novel missense mutations, p.R11C and p.R12C, in CRYAB associated with autosomal recessive congenital nuclear cataracts.
authors.affiliation: Ophthalmic Genetics and Visual Function Branch, National Eye Institute, National Institutes of Health, Bethesda, MD, 20892, United States of America.
authors.forename: Xiaodong
authors.initials: X
authors.lastname: Jiao
authors.affiliation: The Wilmer Eye Institute, Johns Hopkins University School of Medicine, Baltimore, MD, 21287, United States of America.
authors.forename: Shahid Y
authors.initials: SY
authors.lastname: Khan
authors.affiliation: The Wilmer Eye Institute, Johns Hopkins University School of Medicine, Baltimore, MD, 21287, United States of America; National Centre of Excellence in Molecular Biology, University of the Punjab, Lahore, 53700, Pakistan.
authors.forename: Bushra
authors.initials: B
authors.lastname: Irum
authors.affiliation: King Khaled Eye Specialist Hospital, Riyadh, 12329, Saudi Arabia.
authors.forename: Arif O
authors.initials: AO
authors.lastname: Khan
authors.affiliation: Ophthalmic Genetics and Visual Function Branch, National Eye Institute, National Institutes of Health, Bethesda, MD, 20892, United States of America.
authors.forename: Qiwei
authors.initials: Q
authors.lastname: Wang
authors.affiliation: The Wilmer Eye Institute, Johns Hopkins University School of Medicine, Baltimore, MD, 21287, United States of America.
authors.forename: Firoz
authors.initials: F
authors.lastname: Kabir
authors.affiliation: National Centre of Excellence in Molecular Biology, University of the Punjab, Lahore, 53700, Pakistan.
authors.forename: Asma A
authors.initials: AA
authors.lastname: Khan
authors.affiliation: National Centre of Excellence in Molecular Biology, University of the Punjab, Lahore, 53700, Pakistan.
authors.forename: Tayyab
authors.initials: T
authors.lastname: Husnain
authors.affiliation: Allama Iqbal Medical College, University of Health Sciences, Lahore, 54550, Pakistan; National Centre for Genetic Diseases, Shaheed Zulfiqar Ali Bhutto Medical University, Islamabad, Pakistan.
authors.forename: Javed
authors.initials: J
authors.lastname: Akram
authors.affiliation: National Centre of Excellence in Molecular Biology, University of the Punjab, Lahore, 53700, Pakistan; Allama Iqbal Medical College, University of Health Sciences, Lahore, 54550, Pakistan; National Centre for Genetic Diseases, Shaheed Zulfiqar Ali Bhutto Medical University, Islamabad, Pakistan.
authors.forename: Sheikh
authors.initials: S
authors.lastname: Riazuddin
authors.affiliation: Ophthalmic Genetics and Visual Function Branch, National Eye Institute, National Institutes of Health, Bethesda, MD, 20892, United States of America.
authors.forename: J Fielding
authors.initials: JF
authors.lastname: Hejtmancik
authors.affiliation: The Wilmer Eye Institute, Johns Hopkins University School of Medicine, Baltimore, MD, 21287, United States of America.
authors.forename: S Amer
authors.initials: SA
authors.lastname: Riazuddin
mesh_terms: D000818:Animals; D002386:Cataract / Q000151:congenital* / Q000175:diagnosis / Q000235:genetics; D002880:Chromosomes, Human, Pair 11; D019295:Computational Biology; D003241:Consanguinity; D004252:DNA Mutational Analysis; D004195:Disease Models, Animal; D019143:Evolution, Molecular; D005091:Exons; D005260:Female; D015870:Gene Expression; D005808:Genes, Recessive; D008040:Genetic Linkage; D006239:Haplotypes; D006801:Humans; D008126:Lod Score; D008297:Male; D051379:Mice; D018895:Microsatellite Repeats; D020125:Mutation, Missense; D010375:Pedigree; D066167:Slit Lamp; D038203:alpha-Crystallin B Chain / Q000737:chemistry / Q000235:genetics*
chemical_list: C059215:CRYAB protein, human; D038203:alpha-Crystallin B Chain