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Delayed onset of congenital hereditary endothelial dystrophy due to compound heterozygous SLC4A11 mutations.

ABSTRACT: Congenital hereditary endothelial dystrophy (CHED) is an autosomal recessive disorder characterized by bilateral, symmetrical, noninflammatory corneal clouding (edema) present at birth or shortly thereafter. This study reports on an unusual delayed presentation of CHED with compound heterozygous SLC4A11 mutations.A 45-year-old female, presenting with bilateral decreased vision since childhood that deteriorated in the last 5 years, was evaluated to rule out trauma, viral illness, chemical injury, glaucoma, and corneal endothelial dystrophies. Tear sample was sent for herpes simplex viral (HSV) antigen testing. Genomic DNA from peripheral blood was screened for mutations in all exons of SLC4A11 by direct sequencing. Full-thickness penetrating keratoplasty was done and corneal button was sent for histopathological examination.Slit-lamp findings revealed bilateral diffuse corneal edema and left eye spheroidal degeneration with scarring. Increased corneal thickness (762 ?m and 854 ?m in the right and left eyes, respectively), normal intraocular pressure (12 mmHg and 16 mmHg in the right and left eyes, respectively), inconclusive confocal scan, and specular microscopy, near normal tear film parameters, were the other clinical features. HSV-polymerase chain reaction was negative. Histopathological examination revealed markedly thickened Descemet's membrane with subepithelial spheroidal degeneration. SLC4A11 screening showed a novel variant p.Ser415Asn, reported mutation p.Cys386Arg and two polymorphisms, all in the heterozygous state and not identified in 100 controls.The study shows, for the first time, compound heterozygous SLC4A11 mutations impair protein function leading to delayed onset of the disease.

SUBMITTER: Kumawat BL

PROVIDER: S-EPMC5026072 | biostudies-literature | 2016 Jul

REPOSITORIES: biostudies-literature

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Delayed onset of congenital hereditary endothelial dystrophy due to compound heterozygous SLC4A11 mutations.

Kumawat Babu Lal BL Gupta Ranjan R Sharma Arundhati A Sen Seema S Gupta Shikha S Tandon Radhika R

Indian journal of ophthalmology 20160701 7

<h4>Background</h4>Congenital hereditary endothelial dystrophy (CHED) is an autosomal recessive disorder characterized by bilateral, symmetrical, noninflammatory corneal clouding (edema) present at birth or shortly thereafter. This study reports on an unusual delayed presentation of CHED with compound heterozygous SLC4A11 mutations.<h4>Materials and methods</h4>A 45-year-old female, presenting with bilateral decreased vision since childhood that deteriorated in the last 5 years, was evaluated to ...[more]

PMID: 27609159

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Project description:PurposeThe purpose of this study was to explore the pathogenicity and function of two novel SLC4A11 variants associated with congenital hereditary endothelial dystrophy (CHED) and to study the function of a SLC4A11 (K263R) mutant in vitro.MethodsOphthalmic examinations were performed on a 28-year-old male proband with CHED. Whole-exome and Sanger sequencing were applied for mutation screening. Bioinformatics and pathogenicity analysis were performed. HEK293T cells were transfected with the plasmids of empty vector, wild-type SLC4A11, and SLC4A11 (K263R) mutant. The transfected cells were treated with SkQ1. Oxygen consumption, cellular reactive oxygen species (ROS) level, mitochondrial membrane potential, and apoptosis rate were measured.ResultsThe proband had poor visual acuity with nystagmus since childhood. Corneal foggy opacity was evident in both eyes. Two novel SLC4A11 variants were detected. Sanger sequencing showed that the proband's father and sister carried c.1464-1G>T variant, and the proband's mother and sister carried c.788A>G (p.Lys263Arg) variant. Based on the American College of Medical Genetics (ACMG) guidelines, SLC4A11 c.1464-1G>T was pathogenic, whereas c.788A>G, p.K263R was a variant of undetermined significance. In vitro, SLC4A11 (K263R) variant increased ROS level and apoptosis rate. Decrease in mitochondrial membrane potential and oxygen consumption rate were remarkable. Furthermore, SkQ1 decreased ROS levels and apoptosis rate but increased mitochondrial membrane potential in the transfected cells.ConclusionsTwo novel heterozygous pathogenic variants of the SLC4A11 gene were identified in a family with CHED. The missense variant SLC4A11 (K263R) caused mitochondrial dysfunction and increased apoptosis in mutant transfected cells. In addition, SkQ1 presented a protective effect suggesting the anti-oxidant might be a novel therapeutic drug.Translational relevanceThis study verified the pathogenicity of 2 novel variants in the SLC4A11 gene in a CHED family and found an anti-oxidant might be a new drug.

Project description:Harboyan syndrome is a degenerative corneal disorder defined as congenital hereditary endothelial dystrophy (CHED) accompanied by progressive, postlingual sensorineural hearing loss. To date, 24 cases from 11 families of various origin (Asian Indian, South American Indian, Sephardi Jewish, Brazilian Portuguese, Dutch, Gypsy, Moroccan, Dominican) have been reported. More than 50% of the reported cases have been associated with parental consanguinity. The ocular manifestations in Harboyan syndrome include diffuse bilateral corneal edema occurring with severe corneal clouding, blurred vision, visual loss and nystagmus. They are apparent at birth or within the neonatal period and are indistinguishable from those characteristic of the autosomal recessive CHED (CHED2). Hearing deficit in Harboyan is slowly progressive and typically found in patients 10-25 years old. There are no reported cases with prelinglual deafness, however, a significant hearing loss in children as young as 4 years old has been detected by audiometry, suggesting that hearing may be affected earlier, even at birth. Harboyan syndrome is caused by mutations in the SLC4A11 gene located at the CHED2 locus on chromosome 20p13-p12, indicating that CHED2 and Harboyan syndrome are allelic disorders. A total of 62 different SLC4A11 mutations have been reported in 98 families (92 CHED2 and 6 Harboyan). All reported cases have been consistent with autosomal recessive transmission. Diagnosis is based on clinical criteria, detailed ophthalmological assessment and audiometry. A molecular confirmation of the clinical diagnosis is feasible. A variety of genetic, metabolic, developmental and acquired diseases presenting with clouding of the cornea should be considered in the differential diagnosis (Peters anomaly, sclerocornea, limbal dermoids, congenital glaucoma). Audiometry must be performed to differentiate Harboyan syndrome from CHED2. Autosomal recessive types of CHED (CHED2 and Harboyan syndrome) should carefully be distinguished from the less severe autosomal dominant type CHED1. The ocular abnormalities in patients with Harboyan syndrome may be treated with topical hyperosmolar solutions. However, corneal transplantation (penetrating keratoplasty) represents definitive treatment. Corneal transplantation produces a substantial visual gain and has a relatively good surgical prognosis. Audiometric monitoring should be offered to all patients with CHED2. Hearing aids may be necessary in adolescence.

Dataset Information

Delayed onset of congenital hereditary endothelial dystrophy due to compound heterozygous SLC4A11 mutations.

Publications

Delayed onset of congenital hereditary endothelial dystrophy due to compound heterozygous SLC4A11 mutations.

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