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Article: ALPK1 missense pathogenic variant in five families leads to ROSAH syndrome, an ocular multisystem autosomal dominant disorder

TitleALPK1 missense pathogenic variant in five families leads to ROSAH syndrome, an ocular multisystem autosomal dominant disorder
Authors
KeywordsRetinal dystrophy
ALPK1
ROSAH syndrome
Ciliogenesis
Genome sequencing
Issue Date2019
PublisherSpringer Nature for American College of Medical Genetics. The Journal's web site is located at http://www.nature.com/gim/index.html
Citation
Genetics In Medicine, 2019 How to Cite?
AbstractPurpose: To 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. Methods: Independent 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. Results: We 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. Conclusion: Heterozygosity for ALPK1, p.Thr237Met leads to ROSAH syndrome, an autosomal dominant ocular systemic disorder.
Persistent Identifierhttp://hdl.handle.net/10722/271919
ISSN
2017 Impact Factor: 9.937
2015 SCImago Journal Rankings: 3.545

 

DC FieldValueLanguage
dc.contributor.authorWlliams, LB-
dc.contributor.authorJaved, A-
dc.contributor.authorSabri, A-
dc.contributor.authorMorgan, DJ-
dc.contributor.authorHuff, CD-
dc.contributor.authorGrigg, JR-
dc.contributor.authorHeng, XT-
dc.contributor.authorKhng, AJ-
dc.contributor.authorHollink, IHIM-
dc.contributor.authorMorrison, MA-
dc.contributor.authorOwen, LA-
dc.contributor.authorAnderson, K-
dc.contributor.authorKinard, K-
dc.contributor.authorGreenlees, R-
dc.contributor.authorNovacic, D-
dc.contributor.authorSen, HN-
dc.contributor.authorZein, WM-
dc.contributor.authorRodgers, GM-
dc.contributor.authorVitale, AT-
dc.contributor.authorHaider, NB-
dc.contributor.authorHillmer, AM-
dc.contributor.authorNg, PC-
dc.contributor.authorShankaracharya-
dc.contributor.authorCheng, A-
dc.contributor.authorZheng, L-
dc.contributor.authorGillies, MC-
dc.contributor.authorvan Slegtenhorst, M-
dc.contributor.authorvan Hagen, PM-
dc.contributor.authorMissotten, TOAR-
dc.contributor.authorFarley, GL-
dc.contributor.authorPolo, M-
dc.contributor.authorMalatack, J-
dc.contributor.authorCurtin, J-
dc.contributor.authorMartin, F-
dc.contributor.authorArbuckle, S-
dc.contributor.authorAlexander, SI-
dc.contributor.authorChircop, M-
dc.contributor.authorDavila, S-
dc.contributor.authorDigre, KB-
dc.contributor.authorJamieson, RV-
dc.contributor.authorDeAngelis, MM-
dc.date.accessioned2019-07-20T10:32:05Z-
dc.date.available2019-07-20T10:32:05Z-
dc.date.issued2019-
dc.identifier.citationGenetics In Medicine, 2019-
dc.identifier.issn1098-3600-
dc.identifier.urihttp://hdl.handle.net/10722/271919-
dc.description.abstractPurpose: To 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. Methods: Independent 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. Results: We 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. Conclusion: Heterozygosity for ALPK1, p.Thr237Met leads to ROSAH syndrome, an autosomal dominant ocular systemic disorder.-
dc.languageeng-
dc.publisherSpringer Nature for American College of Medical Genetics. The Journal's web site is located at http://www.nature.com/gim/index.html-
dc.relation.ispartofGenetics In Medicine-
dc.rightsThis work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License.-
dc.subjectRetinal dystrophy-
dc.subjectALPK1-
dc.subjectROSAH syndrome-
dc.subjectCiliogenesis-
dc.subjectGenome sequencing-
dc.titleALPK1 missense pathogenic variant in five families leads to ROSAH syndrome, an ocular multisystem autosomal dominant disorder-
dc.typeArticle-
dc.identifier.emailJaved, A: javed@hku.hk-
dc.identifier.authorityJaved, A=rp02386-
dc.description.naturepublished_or_final_version-
dc.identifier.doi10.1038/s41436-019-0476-3-
dc.identifier.pmid30967659-
dc.identifier.scopuseid_2-s2.0-85064044010-
dc.identifier.hkuros298456-
dc.publisher.placeUnited States-

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