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Genet Med. 2019 Sep;21(9):2103-2115. doi: 10.1038/s41436-019-0476-3. Epub 2019 Apr 10.

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

Author information

1
Department of Ophthalmology and Visual Sciences, John A Moran Eye Center, University of Utah School of Medicine, Salt Lake City, UT, USA.
2
Genome Institute of Singapore, Singapore, Singapore.
3
School of Biomedical Sciences, The University of Hong Kong, Hong Kong, Hong Kong.
4
Eye Genetics Research Unit, Children's Medical Research Institute, The Children's Hospital at Westmead, Save Sight Institute, University of Sydney, Sydney, NSW, Australia.
5
Department of Epidemiology, Division of OVP, Cancer Prevention and Population Sciences, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
6
Discipline of Ophthalmology, University of Sydney, Sydney, NSW, Australia.
7
Department of Clinical Genetics, Erasmus MC, Rotterdam, The Netherlands.
8
Drs. Farley, Polo and Ho, Colonial Heights, VA, USA.
9
National Institutes of Health, National Human Genome Research Institute, Undiagnosed Diseases Network, Bethesda, MD, USA.
10
National Eye Institute, National Institutes of Health, Bethesda, MD, USA.
11
Department of Hematology, Utah Health Sciences Center, Salt Lake City, UT, USA.
12
Department of Ophthalmology, Schepens Eye Research Institute/Massachusetts Eye and Ear, Harvard Medical School, Boston, MA, USA.
13
Department of Immunology, Erasmus MC, Rotterdam, The Netherlands.
14
The Rotterdam Eye Hospital, Rotterdam, The Netherlands.
15
Nemours/Alfred I. DuPont Hospital for Children, Wilmington, DE, USA.
16
Department of Haematology, The Children's Hospital at Westmead, Sydney, NSW, Australia.
17
Department of Ophthalmology, The Children's Hospital at Westmead, Sydney, NSW, Australia.
18
Department of Pathology, The Children's Hospital at Westmead, Sydney, NSW, Australia.
19
Department of Nephrology, The Children's Hospital at Westmead, Sydney, NSW, Australia.
20
Cell Cycle Unit, Children's Medical Research Institute, University of Sydney, Sydney, NSW, Australia.
21
Eye Genetics Research Unit, Children's Medical Research Institute, The Children's Hospital at Westmead, Save Sight Institute, University of Sydney, Sydney, NSW, Australia. rjamieson@cmri.org.au.
22
Disciplines of Genomic Medicine, and Child and Adolescent Health, Faculty of Medicine and Health, University of Sydney, Sydney, NSW, Australia. rjamieson@cmri.org.au.
23
Department of Clinical Genetics, Western Sydney Genetics Program, The Children's Hospital at Westmead, Sydney Children's Hospitals Network, Sydney, NSW, Australia. rjamieson@cmri.org.au.
24
Department of Ophthalmology and Visual Sciences, John A Moran Eye Center, University of Utah School of Medicine, Salt Lake City, UT, USA. margaret.deangelis@utah.edu.
25
Department of Pharmacotherapy, College of Pharmacy, University of Utah, Salt Lake City, UT, USA. margaret.deangelis@utah.edu.
26
Department of Population Health Sciences, University of Utah School of Medicine, Salt Lake City, UT, USA. margaret.deangelis@utah.edu.

Abstract

PURPOSE:

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.

KEYWORDS:

ALPK1; ROSAH syndrome; ciliogenesis; genome sequencing; retinal dystrophy

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