Journal article
Homozygous missense variants in YKT6 result in loss of function and are associated with developmental delay, with or without severe infantile liver disease and risk for hepatocellular carcinoma
Genetics in medicine, Vol.26(7), 101125
07/2024
DOI: 10.1016/j.gim.2024.101125
PMCID: PMC11335040
PMID: 38522068
Abstract
YKT6 plays important roles in multiple intracellular vesicle trafficking events but has not been associated with Mendelian diseases.
We report three unrelated individuals with rare homozygous missense variants in YKT6 who exhibited neurological disease with or without a progressive infantile liver disease. We modeled the variants in Drosophila. We generated wild-type and variant genomic rescue constructs (GRs) of the fly ortholog dYkt6 and compared their ability in rescuing the loss-of-function phenotypes in mutant flies. We also generated a dYkt6
allele to assess the expression pattern of dYkt6.
Two individuals are homozygous for YKT6 [NM_006555.3:c.554A>G p.(Tyr185Cys)] and exhibited normal prenatal course followed by failure to thrive, developmental delay and progressive liver disease. Haplotype analysis identified a shared homozygous region flanking the variant, suggesting a common ancestry. The third individual is homozygous for YKT6 [NM_006555.3:c.191A>G p.(Tyr64Cys)] and exhibited neurodevelopmental disorders and optic atrophy. Fly dYkt6 is essential and is expressed in the fat body (analogous to liver) and central nervous system. Wild-type GR can rescue the lethality and autophagic flux defects whereas the variants are less efficient in rescuing the phenotypes.
The YKT6 variants are partial loss-of-function alleles and the p.(Tyr185Cys) is more severe than p.(Tyr64Cys).
Details
- Title: Subtitle
- Homozygous missense variants in YKT6 result in loss of function and are associated with developmental delay, with or without severe infantile liver disease and risk for hepatocellular carcinoma
- Creators
- Mengqi MaMythily Ganapathi - Columbia University Irving Medical CenterYiming ZhengKai-Li TanOguz Kanca - Baylor College of MedicineKevin E Bove - Cincinnati Children's Hospital Medical CenterNorma Quintanilla - Baylor College of MedicineSebnem O Sag - Bursa Uludağ Üni̇versi̇tesi̇Sehime G Temel - Bursa Uludağ Üni̇versi̇tesi̇Charles A LeDuc - Columbia UniversityAmanda J McPartland - Columbia UniversityElaine M Pereira - Columbia UniversityYufeng Shen - Columbia University Irving Medical CenterJacob Hagen - Columbia University Irving Medical CenterChristie P Thomas - University of IowaNhu Thao Nguyen Galván - Baylor College of MedicineXueyang PanShenzhao LuJill A RosenfeldDaniel G CalameMichael F WanglerJames R LupskiDavut PehlivanPaula M HertelWendy K Chung - Boston Children's HospitalHugo J Bellen
- Resource Type
- Journal article
- Publication Details
- Genetics in medicine, Vol.26(7), 101125
- DOI
- 10.1016/j.gim.2024.101125
- PMID
- 38522068
- PMCID
- PMC11335040
- NLM abbreviation
- Genet Med
- ISSN
- 1098-3600
- eISSN
- 1530-0366
- Publisher
- ELSEVIER SCIENCE INC
- Grant note
- DOI: 10.13039/100016958, name: National Institutes of Health Office of Research Infrastructure Programs; DOI: 10.13039/100001819, name: International Rett Syndrome Foundation; DOI: 10.13039/100000862, name: Doris Duke Charitable Foundation; DOI: 10.13039/100000051, name: National Human Genome Research Institute; DOI: 10.13039/100000052, name: NIH Office of the Director; DOI: 10.13039/100009633, name: National Institute of Child Health and Human Development; DOI: 10.13039/100000065, name: National Institute of Neurological Disorders and Stroke
- Language
- English
- Electronic publication date
- 03/21/2024
- Date published
- 07/2024
- Academic Unit
- Stead Family Department of Pediatrics; Obstetrics and Gynecology; Nephrology; Internal Medicine
- Record Identifier
- 9984577124002771
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