Mutations in c10orf11, a melanocyte-differentiation gene, cause autosomal-recessive albinism.

Autosomal-recessive albinism is a hypopigmentation disorder with a broad phenotypic range. A substantial fraction of individuals with albinism remain genetically unresolved, and it has been hypothesized that more genes are to be identified. By using homozygosity mapping of an inbred Faroese family, we identified a 3.5 Mb homozygous region (10q22.2-q22.3) on chromosome 10. The region contains five protein-coding genes, and sequencing of one of these, C10orf11, revealed a nonsense mutation that segregated with the disease and showed a recessive inheritance pattern. Investigation of additional albinism-affected individuals from the Faroe Islands revealed that five out of eight unrelated affected persons had the nonsense mutation in C10orf11. Screening of a cohort of autosomal-recessive-albinism-affected individuals residing in Denmark showed a homozygous 1 bp duplication in C10orf11 in an individual originating from Lithuania. Immunohistochemistry showed localization of C10orf11 in melanoblasts and melanocytes in human fetal tissue, but no localization was seen in retinal pigment epithelial cells. Knockdown of the zebrafish (Danio rerio) homolog with the use of morpholinos resulted in substantially decreased pigmentation and a reduction of the apparent number of pigmented melanocytes. The morphant phenotype was rescued by wild-type C10orf11, but not by mutant C10orf11. In conclusion, we have identified a melanocyte-differentiation gene, C10orf11, which when mutated causes autosomal-recessive albinism in humans.

Autosomal-recessive posterior microphthalmos is caused by mutations in PRSS56, a gene encoding a trypsin-like serine protease.

Posterior microphthalmos (MCOP) is a rare isolated developmental anomaly of the eye characterized by extreme hyperopia due to short axial length. The population of the Faroe Islands shows a high prevalence of an autosomal-recessive form (arMCOP) of the disease. Based on published linkage data, we refined the position of the disease locus (MCOP6) in an interval of 250 kb in chromosome 2q37.1 in two large Faroese families. We detected three different mutations in PRSS56. Patients of the Faroese families were either homozygous for c.926G>C (p.Trp309Ser) or compound heterozygous for c.926G>C and c.526C>G (p.Arg176Gly), whereas a homozygous 1 bp duplication (c.1066dupC) was identified in five patients with arMCOP from a consanguineous Tunisian family. In one patient with MCOP from the Faroe Islands and in another one from Turkey, no PRSS56 mutation was detected, suggesting nonallelic heterogeneity of the trait. Using RT-PCR, PRSS56 transcripts were detected in samples derived from the human adult retina, cornea, sclera, and optic nerve. The expression of the mouse ortholog could be first detected in the eye at E17 and was maintained into adulthood. The predicted PRSS56 protein is a 603 amino acid long secreted trypsin-like serine peptidase. The c.1066dupC is likely to result in a functional null allele, whereas the two point mutations predict the replacement of evolutionary conserved and functionally important residues. Molecular modeling of the p.Trp309Ser mutant suggests that both the affinity and reactivity of the enzyme toward in vivo protein substrates are likely to be substantially reduced.

Prevalence of Open-angle Glaucoma in the Faroese Population.

PURPOSE: The Faroe Islands are home to 50,000 genetically isolated people in the North Atlantic. The prevalence of open-angle glaucoma (OAG) in the Faroese population is unknown. Consequently, we conducted a survey to determine the prevalence of OAG in the Faroese population. We also investigated the role of known glaucoma-causing genes in Faroese OAG. MATERIALS AND METHODS: We conducted a prospective survey of known and newly diagnosed glaucoma patients at the Faroese National Hospital, Landssjukrahusid, Tórshavn between October 1, 2015 to December 31, 2017. In addition we reviewed the only eye care provider in the Faroese Islands by scrutinizing electronic medical records between 2009 and June 15, 2014, October 1, 2015 and the partly overlapping prescriptions for ocular hypotensive medications in 2016 to identify patients with either a diagnosis of glaucoma, a diagnosis of ocular hypertension or a prescription for ocular hypotensive medications. Next, we prospectively confirmed diagnoses with complete eye examinations. Patient DNA samples were tested for variations in known glaucoma-causing genes [myocilin (MYOC), optineurin (OPTN), and TANK binding kinase 1 (TBK1)]. RESULTS: We determined the age-related prevalence of OAG January 1, 2017 in individuals 40 years or older to be 10.7/1000 (1.07%) and highly age-related. A diagnosis of OAG was present in 264 patients, of whom 211 (79.9%) had primary OAG (including normal tension glaucoma), 49 (18.6%) had pseudoexfoliation glaucoma, and 4 (1.5%) had pigmentary glaucoma. Among patients receiving medications for glaucoma, nearly 50% had primary OAG, while the majority of the rest had ocular hypertension or secondary glaucoma. No disease-causing variants were detected in MYOC, OPTN, or TBK1. CONCLUSIONS: The calculated prevalence of OAG in the Faroe Islands was 1.07%. The absence of MYOC, OPTN, or TBK1 disease-causing variants in Faroese primary OAG patients suggests that a different, potentially unique set of genes may be contributing to the pathogenesis of glaucoma in this population.

A novel MERTK deletion is a common founder mutation in the Faroe Islands and is responsible for a high proportion of retinitis pigmentosa cases.

PURPOSE: The aim of the study was to elucidate the genetic background of retinitis pigmentosa (RP) in a Faroe Islands population, a genetic isolate in the North Atlantic Ocean. METHODS: Blood samples were collected from subjects diagnosed with RP and their families. DNA from affected individuals underwent single nucleotide polymorphism microarray analysis and homozygosity mapping followed by sequence analysis of candidate genes. RESULTS: We identified 25 cases of nonsyndromic RP corresponding to a prevalence of 1 in 1,900. Single nucleotide polymorphism analysis revealed a homozygous region on chromosome 2q, common to patients in four families, which harbored the RP gene MER tyrosine kinase protooncogene (MERTK). A deletion of 91 kb was identified in seven patients, representing 30% of the analyzed Faroese cases of nonsyndromic RP. The clinical course of six patients who were homozygous for the deletion showed onset in the first decade followed by a rapid deterioration of both rod and cone photoreceptor function. Early macular involvement was present, in accordance with that of other reported patients with MERTK mutations. CONCLUSIONS: Previous studies have shown a frequency of less than 1% of MERTK mutations in RP patients. The 91-kb deletion encompassing exons 1-7 of MERTK is a common founder mutation in the Faroe Islands, responsible for around 30% of RP, and together with mutations in protocadherin 21 (PCDH21) accounts for more than half of the retinal dystrophy cases.

Hereditary high hypermetropia in the Faroe Islands.

PURPOSE: To characterize the phenotype of two families with high hypermetropia from the Faroe Islands. METHODS: Ophthalmologic evaluation including ultrasound oculometry and anthropometric measurements. RESULTS: Of the 40 examined family members, 15 individuals (8 males, 7 females; ages: 6-77 years; mean: 36.5 years) had small deep-set eyes with high hypermetropia (median: + 16.5 D; range: + 7.75 to + 22), short axial eye length (< 21 mm), and a thickened eye wall. The median corrected visual acuity was 0.4 (0.2-0.9). Ocular complications included angle-closure glaucoma in six eyes, uveal effusion in three eyes, cataract in two eyes, and esotropia with amblyopia in three eyes. An emergency case of uveal effusion and retinal detachment after Yag iridotomy eventually responded to systemic corticosteroids and scleral resection surgery with a slow visual recovery. No associated ocular or systemic malformations were found in the series. In addition to the two examined families, six smaller Faroese families with high hypermetropia are briefly reported. CONCLUSIONS: The study highlights the signs and symptoms of a rare hereditary phenotype characterized by a short axial length mainly confined to the posterior segment of the eye, a shallow anterior chamber, and a thickened eye wall. The morphological characteristics predispose for sight-threatening complications such as angle-closure glaucoma, chorioretinal pathology including uveal effusion, and amblyopia. Regular ophthalmic follow-up is therefore of obvious importance in families known to have small eyes/high hypermetropia. An endemic high prevalence in the Faroe Islands suggests the presence of a founder effect, and further genetic research would probably indicate pseudodominant rather than dominant transmission