Analysis of mutations in the CX46, CX50 and HSF4 genes in patients with congenital cataract

Author(s)

Ana Luíza de Araújo

• Document type: Master's Dissertation
• Press: Campinas, SP.
• Institution: Universidade Estadual de Campinas (UNICAMP). Instituto de Biologia
• Defense date: 2015-03-08

Examining board members

Mônica Barbosa de Melo; Carmen Sílvia Bertuzzo; Mônica Alves

• Advisor: Mônica Barbosa de Melo

Abstract

Congenital cataract is the leading cause of reversible blindness in childhood, with a prevalence of one to five cases per 10.000 live births. The hereditary form corresponds to about 50% of these cases, and the autosomal dominant inheritance is the most frequent. The genetic alterations responsible for non-syndromic congenital cataracts lead to changes in lens proteins, such as crystallins, membrane transport proteins, like connexins, and cytoskeletal proteins, besides alterations in genes related to ocular development (for example, HSF4). Nuclear and lamellar cataracts are two of the most common forms of congenital opacities, and alterations in the CX46 and CX50 genes, that encode connexin proteins, have been related to the nuclear phenotype, while alterations in the HSF4 gene have been associated with the lamellar phenotype. The present study aimed to determine mutations in the CX46, CX50 and HSF4 genes in Brazilian families with nuclear and lamellar bilateral congenital cataracts, previously investigated for the CRYAA, CRYGC and CRYGD genes. The ophthalmological examination and the molecular analysis were performed in 78 individuals belonging to eleven families followed in the congenital cataract ambulatory of the Clinical Hospital, University of Campinas (UNICAMP). The coding regions and the intron/exon boundaries were evaluated through Polymerase Chain Reaction (PCR) and direct sequencing. Nineteen alterations were identified in the three evaluated genes, five of those being novel. The P59L mutation in the CX46 gene and the W45L, D47H and P280R mutations in the CX50 gene were predicted to be probably damaging to the protein function, and segregated with the disease in families 1 (D47H), 3 (P59L), 8 (P280R), 9 (W45L) and 11 (D47H). Thus, it was possible to identify four probably causal mutations in five of the eleven families studied, all of them in the connexin genes, demonstrating the importance of these proteins in maintaining the transparency of the lens. The mutations identified in the connexin 46 and 50 can explain 45,45% of the hereditary nuclear and lamellar congenital cataract in this sample of the population from the southeastern Brazil (AU)

• FAPESP's process: 13/05316-6 - ANALYSIS OF STRUCTURAL ALTERATIONS IN THE CX46, CX50 AND HSF4 GENES IN PATIENTS WITH CONGENITAL CATARACT
• Grantee: Ana Luiza de Araujo
• Support Opportunities: Scholarships in Brazil - Master