Absence of phenotype-genotype correlation of patients expressing mutations in the SLC4A11 gene.

PURPOSE: The purposes of this study were to describe the clinical characteristics of corneal patients with mutations in the SLC4A11 gene and to determine if these characteristics could be correlated with specific genetic mutations. METHODS: A retrospective case series review was conducted. Baseline demographic data, including gender, age at diagnosis of congenital hereditary endothelial dystrophy, family history, and pedigree information, were obtained. Information from clinical examination, including intraocular pressure, ultrasonic pachymetry, best spectacle-corrected visual acuity, axial length, and slit-lamp biomicroscopic evaluation, including corneal diameter and fundus examination, were also documented from the notes. History of corneal surgery was also recorded. Hearing loss was assessed by audiometry. Genetic analysis was performed by polymerase chain reaction amplification and sequencing. RESULTS: Seven patients were identified. Four of the seven had associated hearing loss; all of the patients had undergone or were awaiting penetrating keratoplasty to one or both eyes. No correlation could be reached between the ocular phenotype and the gene mutation in this small sample. Individuals with the same mutation had different degrees of hearing loss within their respective families. CONCLUSIONS: Corneal endothelial cells are more vulnerable to defects in the functional activity of SLC4A11 than cells of the striae vascularis of the inner ear. Both congenital hereditary endothelial dystrophy 2 and Harboyan syndrome have similar ocular phenotypes, ie, diffuse bilateral corneal edema present at birth or within the neonatal period; hence, audiometry must be performed to differentiate the two conditions.

Genetic analysis of patients with Fuchs endothelial corneal dystrophy in India.

BACKGROUND: Mutations in COL8A2 gene which encodes the collagen alpha-2 (VIII) chain have been identified in both familial and sporadic cases of Fuchs endothelial corneal dystrophy (FECD). Heterozygous mutations in the SLC4A11 gene are also known to cause late-onset FECD. Therefore we screened for COL8A2, SLC4A11 gene variants in Indian FECD patients. METHODS: Eighty patients with clinically diagnosed FECD and 100 age matched normal individuals were recruited. Genomic DNA was isolated from peripheral blood leukocytes. Mutations in COL8A2, SLC4A11 coding regions were screened using bi-directional sequencing. Fischer's exact test or Pearson's chi squared test were used to predict the statistical association of genotypes with the phenotype. RESULTS: Screening of COL8A2 gene revealed 2 novel c.1610G>A, c.1643A>G and 3 reported variations c.112G>A, c.464G>A and c.1485G>A. In SLC4A11 gene, novel c.1659C>T, c.1974C>T and reported c.405G>A, c.481A>C and c.639G>A variants were identified. However all the variations in both the genes were also present in unaffected controls. CONCLUSIONS: This is the first study analysing COL8A2 gene in Indian patients with FECD. No pathogenic mutations were identified in COL8A2. Merely silent changes, which showed statistically insignificant association with FECD, were identified in the screening of SLC4A11 gene. These results suggest that COL8A2, SLC4A11 genes may not be responsible for FECD in patients examined in this study.

Identification of mutations in the SLC4A11 gene in patients with recessive congenital hereditary endothelial dystrophy.

OBJECTIVE: To identify Solute Carrier family 4 (sodium borate cotransporter) member 11 (SLC4A11) gene mutations associated with autosomal recessive congenital hereditary endothelial dystrophy (CHED2). METHODS: DNA extraction from blood, polymerase chain reaction amplification, and direct sequencing of all the exons of the SLC4A11 gene were performed for 26 affected members of 20 unrelated families with CHED2. RESULTS: Of 10 mutations observed, 6 were novel, 1 of which involves a complete deletion of exon 6, identified for the first time, to our knowledge, in SLC4A11. The mutations cosegregated with the disease phenotype and were absent in 200 ethnically matched control chromosomes analyzed. CONCLUSIONS: This study increases the number of SLC4A11 gene mutations and confirms the role of this gene in causing CHED2. Clinical examination did not reveal any considerable variability in disease expressivity in patients carrying SLC4A11 mutations. Extensive linkage analysis may reveal the modifier genes involved in causing CHED2 in the SLC4A11 mutations unidentified in 9 families. CLINICAL RELEVANCE: In India, there is a high frequency of CHED2, possibly related to consanguineous marriages. Counseling could be provided to explain the drawbacks of consanguineous marriages to assist in reducing this devastating disorder.

Mutations in sodium-borate cotransporter SLC4A11 cause recessive congenital hereditary endothelial dystrophy (CHED2).

Congenital hereditary endothelial dystrophy (CHED) is a heritable, bilateral corneal dystrophy characterized by corneal opacification and nystagmus. We describe seven different mutations in the SLC4A11 gene in ten families with autosomal recessive CHED. Mutations in SLC4A11, which encodes a membrane-bound sodium-borate cotransporter, cause loss of function of the protein either by blocking its membrane targeting or nonsense-mediated decay.