Abstract
PurposeTo identify the molecular cause in five unrelated families with a distinct autosomal dominant ocular systemic disorder we called ROSAH syndrome due to clinical features of retinal dystrophy, optic nerve edema, splenomegaly, anhidrosis, and migraine headache. MethodsIndependent discovery exome and genome sequencing in families 1, 2, and 3, and confirmation in families 4 and 5. Expression of wild-type messenger RNA and protein in human and mouse tissues and cell lines. Ciliary assays in fibroblasts from affected and unaffected family members. ResultsWe found the heterozygous missense variant in the ɑ-kinase gene, ALPK1, (c.710C>T, [p.Thr237Met]), segregated with disease in all five families. All patients shared the ROSAH phenotype with additional low-grade ocular inflammation, pancytopenia, recurrent infections, and mild renal impairment in some. ALPK1 was notably expressed in retina, retinal pigment epithelium, and optic nerve, with immunofluorescence indicating localization to the basal body of the connecting cilium of the photoreceptors, and presence in the sweat glands. Immunocytofluorescence revealed expression at the centrioles and spindle poles during metaphase, and at the base of the primary cilium. Affected family member fibroblasts demonstrated defective ciliogenesis. ConclusionHeterozygosity for ALPK1, p.Thr237Met leads to ROSAH syndrome, an autosomal dominant ocular systemic disorder.
Highlights
Retinal dystrophy describes progressive degeneration or abnormality of photoreceptors leading to vision loss, with a worldwide prevalence of approximately 1 in 3500
Heterozygosity for ALPK1, p.Thr237Met leads to ROSAH syndrome, an autosomal dominant ocular systemic disorder
We propose the name ROSAH syndrome, due to the consistency of the ophthalmic, hematologic, and systemic signs, and detailed clinical case reports are provided in the Supplementary Clinical Information Appendix
Summary
Retinal dystrophy describes progressive degeneration or abnormality of photoreceptors (rods and cones) leading to vision loss, with a worldwide prevalence of approximately 1 in 3500 (ref. 1). Retinal dystrophy describes progressive degeneration or abnormality of photoreceptors (rods and cones) leading to vision loss, with a worldwide prevalence of approximately 1 in 3500 Syndromal forms include metabolic conditions such as Refsum disease (MIM 266500), storage disorders such as neuronal ceroid lipofuscinosis 3. (MIM 204200), and conditions where there are primary ciliary abnormalities including Bardet–Biedl (MIM 209900), Senior–Løken (MIM 266900), and Joubert syndromes (MIM 213300) The features common to all three affected individuals in this family included a severe retinal dystrophy of the cones and rods, optic nerve edema, mild pancytopenia, and idiopathic massive splenomegaly. Despite extensive literature search and discussion with colleagues, no other affected individuals were identified at that time
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