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

Lloyd B Williams; Asif Javed; Amin Sabri; Denise J Morgan; Chad D Huff; John R Grigg; Xiu Ting Heng; Alexis J Khng; Iris H I M Hollink; Margaux A Morrison; Leah A Owen; Katherine Anderson; Krista Kinard; Rebecca Greenlees; Danica Novacic; H Nida Sen; Wadih M Zein; George M Rodgers; Albert T Vitale; Neena B Haider; Axel M Hillmer; Pauline C Ng; null Shankaracharya; Anson Cheng; Linda Zheng; Mark C Gillies; Marjon van Slegtenhorst; P Martin van Hagen; Tom O A R Missotten; Gary L Farley; Michael Polo; James Malatack; Julie Curtin; Frank Martin; Susan Arbuckle; Stephen I Alexander; Megan Chircop; Sonia Davila; Kathleen B Digre; Robyn V Jamieson; Margaret M DeAngelis

doi:10.1038/s41436-019-0476-3

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

Lloyd B Williams, Asif Javed, Amin Sabri, Denise J Morgan, Chad D Huff, John R Grigg, Xiu Ting Heng, Alexis J Khng, Iris H I M Hollink, Margaux A Morrison, Leah A Owen, Katherine Anderson, Krista Kinard, Rebecca Greenlees, Danica Novacic, H Nida Sen, Wadih M Zein, George M Rodgers, Albert T Vitale, Neena B HaiderAxel M Hillmer, Pauline C Ng, Shankaracharya, Anson Cheng, Linda Zheng, Mark C Gillies, Marjon van Slegtenhorst, P Martin van Hagen, Tom O A R Missotten, Gary L Farley, Michael Polo, James Malatack, Julie Curtin, Frank Martin, Susan Arbuckle, Stephen I Alexander, Megan Chircop, Sonia Davila, Kathleen B Digre, Robyn V Jamieson, Margaret M DeAngelis

Medical retina and Uveitis

Research output: Contribution to journal › Article › Research › peer-review

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.

Original language	English
Pages (from-to)	2103-2115
Number of pages	13
Journal	Genetics in medicine : official journal of the American College of Medical Genetics
Volume	21
Issue number	9
DOIs	https://doi.org/10.1038/s41436-019-0476-3
Publication status	Published - Sept 2019

Keywords

Exome/genetics
Female
Heterozygote
Humans
Hypohidrosis/genetics
Male
Migraine Disorders/genetics
Mutation, Missense/genetics
Optic Nerve/metabolism
Pedigree
Phenotype
Protein Kinases/genetics
Retina/metabolism
Retinal Dystrophies/genetics
Splenomegaly/genetics

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Williams, L. B., Javed, A., Sabri, A., Morgan, D. J., Huff, C. D., Grigg, J. R., Heng, X. T., Khng, A. J., Hollink, I. H. I. M., Morrison, M. A., Owen, L. A., Anderson, K., Kinard, K., Greenlees, R., Novacic, D., Nida Sen, H., Zein, W. M., Rodgers, G. M., Vitale, A. T., ... DeAngelis, M. M. (2019). ALPK1 missense pathogenic variant in five families leads to ROSAH syndrome, an ocular multisystem autosomal dominant disorder. Genetics in medicine : official journal of the American College of Medical Genetics, 21(9), 2103-2115. https://doi.org/10.1038/s41436-019-0476-3

@article{61ac8e364b7c4d548a3dd58c860fdb03,

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

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 = "Exome/genetics, Female, Heterozygote, Humans, Hypohidrosis/genetics, Male, Migraine Disorders/genetics, Mutation, Missense/genetics, Optic Nerve/metabolism, Pedigree, Phenotype, Protein Kinases/genetics, Retina/metabolism, Retinal Dystrophies/genetics, Splenomegaly/genetics",

author = "Williams, {Lloyd B} and Asif Javed and Amin Sabri and Morgan, {Denise J} and Huff, {Chad D} and Grigg, {John R} and Heng, {Xiu Ting} and Khng, {Alexis J} and Hollink, {Iris H I M} and Morrison, {Margaux A} and Owen, {Leah A} and Katherine Anderson and Krista Kinard and Rebecca Greenlees and Danica Novacic and {Nida Sen}, H and Zein, {Wadih M} and Rodgers, {George M} and Vitale, {Albert T} and Haider, {Neena B} and Hillmer, {Axel M} and Ng, {Pauline C} and Shankaracharya and Anson Cheng and Linda Zheng and Gillies, {Mark C} and {van Slegtenhorst}, Marjon and {van Hagen}, {P Martin} and Missotten, {Tom O A R} and Farley, {Gary L} and Michael Polo and James Malatack and Julie Curtin and Frank Martin and Susan Arbuckle and Alexander, {Stephen I} and Megan Chircop and Sonia Davila and Digre, {Kathleen B} and Jamieson, {Robyn V} and DeAngelis, {Margaret M}",

year = "2019",

month = sep,

doi = "10.1038/s41436-019-0476-3",

language = "English",

volume = "21",

pages = "2103--2115",

number = "9",

}

Williams, LB, Javed, A, Sabri, A, Morgan, DJ, Huff, CD, Grigg, JR, Heng, XT, Khng, AJ, Hollink, IHIM, Morrison, MA, Owen, LA, Anderson, K, Kinard, K, Greenlees, R, Novacic, D, Nida Sen, H, Zein, WM, Rodgers, GM, Vitale, AT, Haider, NB, Hillmer, AM, Ng, PC, Shankaracharya, Cheng, A, Zheng, L, Gillies, MC, van Slegtenhorst, M, van Hagen, PM, Missotten, TOAR, Farley, GL, Polo, M, Malatack, J, Curtin, J, Martin, F, Arbuckle, S, Alexander, SI, Chircop, M, Davila, S, Digre, KB, Jamieson, RV & DeAngelis, MM 2019, 'ALPK1 missense pathogenic variant in five families leads to ROSAH syndrome, an ocular multisystem autosomal dominant disorder', Genetics in medicine : official journal of the American College of Medical Genetics, vol. 21, no. 9, pp. 2103-2115. https://doi.org/10.1038/s41436-019-0476-3

ALPK1 missense pathogenic variant in five families leads to ROSAH syndrome, an ocular multisystem autosomal dominant disorder. / Williams, Lloyd B; Javed, Asif; Sabri, Amin et al.
In: Genetics in medicine : official journal of the American College of Medical Genetics, Vol. 21, No. 9, 09.2019, p. 2103-2115.

Research output: Contribution to journal › Article › Research › peer-review

TY - JOUR

T1 - ALPK1 missense pathogenic variant in five families leads to ROSAH syndrome, an ocular multisystem autosomal dominant disorder

AU - Williams, Lloyd B

AU - Javed, Asif

AU - Sabri, Amin

AU - Morgan, Denise J

AU - Huff, Chad D

AU - Grigg, John R

AU - Heng, Xiu Ting

AU - Khng, Alexis J

AU - Hollink, Iris H I M

AU - Morrison, Margaux A

AU - Owen, Leah A

AU - Anderson, Katherine

AU - Kinard, Krista

AU - Greenlees, Rebecca

AU - Novacic, Danica

AU - Nida Sen, H

AU - Zein, Wadih M

AU - Rodgers, George M

AU - Vitale, Albert T

AU - Haider, Neena B

AU - Hillmer, Axel M

AU - Ng, Pauline C

AU - Shankaracharya, null

AU - Cheng, Anson

AU - Zheng, Linda

AU - Gillies, Mark C

AU - van Slegtenhorst, Marjon

AU - van Hagen, P Martin

AU - Missotten, Tom O A R

AU - Farley, Gary L

AU - Polo, Michael

AU - Malatack, James

AU - Curtin, Julie

AU - Martin, Frank

AU - Arbuckle, Susan

AU - Alexander, Stephen I

AU - Chircop, Megan

AU - Davila, Sonia

AU - Digre, Kathleen B

AU - Jamieson, Robyn V

AU - DeAngelis, Margaret M

PY - 2019/9

Y1 - 2019/9

N2 - 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.

AB - 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.

KW - Exome/genetics

KW - Female

KW - Heterozygote

KW - Humans

KW - Hypohidrosis/genetics

KW - Male

KW - Migraine Disorders/genetics

KW - Mutation, Missense/genetics

KW - Optic Nerve/metabolism

KW - Pedigree

KW - Phenotype

KW - Protein Kinases/genetics

KW - Retina/metabolism

KW - Retinal Dystrophies/genetics

KW - Splenomegaly/genetics

U2 - 10.1038/s41436-019-0476-3

DO - 10.1038/s41436-019-0476-3

M3 - Article

C2 - 30967659

SN - 1098-3600

VL - 21

SP - 2103

EP - 2115

JO - Genetics in medicine : official journal of the American College of Medical Genetics

JF - Genetics in medicine : official journal of the American College of Medical Genetics

IS - 9

ER -

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

Abstract

Keywords

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