DYNC2H1hypomorphic or retina-predominant variants cause nonsyndromic retinal degeneration

被引：35

作者：

Vig, Anjali ^{[1
]}

Poulter, James A. ^{[3
]}

Ottaviani, Daniele ^{[4
]}

Tavares, Erika ^{[1
]}

Toropova, Katerina ^{[5
]}

Tracewska, Anna Maria ^{[6
,7
]}

Mollica, Antonio ^{[1
]}

Kang, Jasmine ^{[1
]}

Kehelwathugoda, Oshini ^{[1
,8
]}

Paton, Tara ^{[1
,8
]}

Maynes, Jason T. ^{[9
]}

Wheway, Gabrielle ^{[10
]}

Arno, Gavin ^{[4
,11
]}

Khan, Kamron N. ^{[3
]}

McKibbin, Martin ^{[3
]}

Toomes, Carmel ^{[3
]}

Ali, Manir ^{[3
]}

Di Scipio, Matteo ^{[1
]}

Li, Shuning ^{[1
]}

Ellingford, Jamie ^{[12
,13
]}

Black, Graeme ^{[12
,14
]}

Webster, Andrew ^{[4
,11
]}

Rydzanicz, Malgorzata ^{[7
]}

Stawinski, Piotr ^{[7
]}

Ploski, Rafal ^{[7
]}

Vincent, Ajoy ^{[1
,2
,15
]}

Cheetham, Michael E. ^{[4
]}

Inglehearn, Chris F. ^{[3
]}

Roberts, Anthony ^{[5
]}

Heon, Elise ^{[1
,2
,15
]}

机构：

[1] Hosp Sick Children, Genet & Genome Biol, Toronto, ON, Canada

[2] Univ Toronto, Inst Med Sci, Toronto, ON, Canada

[3] St James Univ Hosp, Dept Ophthalmol, Leeds, W Yorkshire, England

[4] UCL Inst Ophthalmol, London, England

[5] Birbeck Univ London, Dept Biol Sci, London, England

[6] LUKASIEWICZ Res Network PORT Polish Ctr Technol D, DNA Anal Unit, Wroclaw, Poland

[7] Med Univ Warsaw, Dept Med Genet, Warsaw, Poland

[8] Hosp Sick Children, Ctr Appl Genom, Toronto, ON, Canada

[9] Hosp Sick Children, Dept Anesthesia & Pain Med, Toronto, ON, Canada

[10] Univ Southampton, Fac Med, Southampton, Hants, England

[11] Moorfields Eye Hosp, London, England

[12] Univ Manchester, Div Evolut & Genom Sci, Fac Biol Med & Hlth, Manchester, Lancs, England

[13] Univ Manchester, Manchester Acad Hlth Sci Ctr MAHSC, Manchester, Lancs, England

[14] Manchester Univ NHS Fdn Trust, St Marys Hosp, Manchester Ctr Genom Med, Manchester, Lancs, England

[15] Hosp Sick Children, Dept Ophthalmol & Vis Sci, Toronto, ON, Canada

来源：

GENETICS IN MEDICINE | 2020年 / 22卷 / 12期

基金：

英国生物技术与生命科学研究理事会; 英国惠康基金; 英国医学研究理事会;

关键词：

inherited retinal disease (IRD); retinitis pigmentosa (RP); primary cilia; intraflagellar transport (IFT); RETROGRADE INTRAFLAGELLAR TRANSPORT; ASPHYXIATING THORACIC DYSTROPHY; CYTOPLASMIC DYNEIN-2; DYNC2H1; MUTATIONS; OUTER SEGMENT; GENES; MECHANISMS; IFT88;

D O I：

10.1038/s41436-020-0915-1

中图分类号：

Q3 [遗传学];

学科分类号：

071007 ; 090102 ;

摘要：

Purpose Determining the role ofDYNC2H1variants in nonsyndromic inherited retinal disease (IRD). Methods Genome and exome sequencing were performed for five unrelated cases of IRD with no identified variant. In vitro assays were developed to validate the variants identified (fibroblast assay, induced pluripotent stem cell [iPSC] derived retinal organoids, and a dynein motility assay). Results Four novelDYNC2H1variants (V1, g.103327020_103327021dup; V2, g.103055779A>T; V3, g.103112272C>G; V4, g.103070104A>C) and one previously reported variant (V5, g.103339363T>G) were identified. In proband 1 (V1/V2), V1 was predicted to introduce a premature termination codon (PTC), whereas V2 disrupted the exon 41 splice donor site causing incomplete skipping of exon 41. V1 and V2 impaired dynein-2 motility in vitro and perturbed IFT88 distribution within cilia. V3, homozygous in probands 2-4, is predicted to cause a PTC in a retina-predominant transcript. Analysis of retinal organoids showed that this new transcript expression increased with organoid differentiation. V4, a novel missense variant, was intranswith V5, previously associated with Jeune asphyxiating thoracic dystrophy (JATD). Conclusion TheDYNC2H1variants discussed herein were either hypomorphic or affecting a retina-predominant transcript and caused nonsyndromic IRD. Dynein variants, specificallyDYNC2H1variants are reported as a cause of non syndromic IRD.

引用

页码：2041 / 2051

页数：11

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