Molecular Genetic Analysis of Pakistani Families With Autosomal Recessive Congenital Cataracts by Homozygosity Screening
| Autor: | Patricia E. Cabrera, Xiaodong Jiao, Javed Akram, Gowthaman Govindarajan, Zilin Zhong, S. Amer Riazuddin, Muhammad Asif Naeem, Wenmin Sun, Shaheen N. Khan, J. Fielding Hejtmancik, Sheikh Riazuddin, Fawad Ur Rahman, Muhammad Zaman Khan Assir, Zaheeruddin A. Qazi, Muhammad Hassaan Ali, Jianjun Chen, Yabin Chen, Qiwei Wang |
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| Rok vydání: | 2017 |
| Předmět: |
Genetic Markers
Male 0301 basic medicine Candidate gene Mutation Missense Genes Recessive genetic analysis Biology medicine.disease_cause Genetic analysis Cataract 03 medical and health sciences Genetic linkage Genetics medicine Humans Protein Isoforms Pakistan Frameshift Mutation Mutation Homozygote Disease gene identification medicine.disease Pedigree 3. Good health consanguineous 030104 developmental biology homozygosity mapping Codon Nonsense Genetic marker Congenital cataracts Microsatellite Female Lod Score autosomal recessive congenital cataracts |
| Zdroj: | Investigative Ophthalmology & Visual Science |
| ISSN: | 1552-5783 |
| Popis: | Purpose To identify the genetic origins of autosomal recessive congenital cataracts (arCC) in the Pakistani population. Methods Based on the hypothesis that most arCC patients in consanguineous families in the Punjab areas of Pakistan should be homozygous for causative mutations, affected individuals were screened for homozygosity of nearby highly informative microsatellite markers and then screened for pathogenic mutations by DNA sequencing. A total of 83 unmapped consanguineous families were screened for mutations in 33 known candidate genes. Results Patients in 32 arCC families were homozygous for markers near at least 1 of the 33 known CC genes. Sequencing the included genes revealed homozygous cosegregating sequence changes in 10 families, 2 of which had the same variation. These included five missense, one nonsense, two frame shift, and one splice site mutations, eight of which were novel, in EPHA2, FOXE3, FYCO1, TDRD7, MIP, GALK1, and CRYBA4. Conclusions The above results confirm the usefulness of homozygosity mapping for identifying genetic defects underlying autosomal recessive disorders in consanguineous families. In our ongoing study of arCC in Pakistan, including 83 arCC families that underwent homozygosity mapping, 3 mapped using genome-wide linkage analysis in unpublished data, and 30 previously reported families, mutations were detected in approximately 37.1% (43/116) of all families studied, suggesting that additional genes might be responsible in the remaining families. The most commonly mutated gene was FYCO1 (14%), followed by CRYBB3 (5.2%), GALK1 (3.5%), and EPHA2 (2.6%). This provides the first comprehensive description of the genetic architecture of arCC in the Pakistani population. |
| Databáze: | OpenAIRE |
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