PUBLICATION
Unravelling the disease mechanism for TSPYL1 deficiency
- Authors
- Buyse, G., Di Michele, M., Wijgaerts, A., Louwette, S., Wittevrongel, C., Thys, C., Downes, K., Ceulemans, B., Van Esch, H., Van Geet, C., Freson, K.
- ID
- ZDB-PUB-201021-7
- Date
- 2020
- Source
- Human molecular genetics 29(20): 3431-3442 (Journal)
- Registered Authors
- Keywords
- none
- MeSH Terms
-
- Animals
- Exome Sequencing
- Female
- Fibroblasts/metabolism
- Fibroblasts/pathology*
- Frameshift Mutation*
- Humans
- Infant
- Infant, Newborn
- Male
- Nuclear Proteins/deficiency*
- Nuclear Proteins/genetics*
- Pedigree
- Phenotype
- Proteome/analysis*
- Sudden Infant Death/genetics
- Sudden Infant Death/pathology*
- Zebrafish
- PubMed
- 33075815 Full text @ Hum. Mol. Genet.
Citation
Buyse, G., Di Michele, M., Wijgaerts, A., Louwette, S., Wittevrongel, C., Thys, C., Downes, K., Ceulemans, B., Van Esch, H., Van Geet, C., Freson, K. (2020) Unravelling the disease mechanism for TSPYL1 deficiency. Human molecular genetics. 29(20):3431-3442.
Abstract
We describe a lethal combined nervous and reproductive systems disease in three affected siblings of a consanguineous family. The phenotype was characterized by visceroautonomic dysfunction (neonatal bradycardia/apnea, feeding problems, hyperactive startle reflex), severe postnatal progressive neurological abnormalities (including abnormal neonatal cry, hypotonia, epilepsy, polyneuropathy, cerebral gray matter atrophy), visual impairment, testicular dysgenesis in males, and sudden death at infant age by brainstem-mediated cardiorespiratory arrest. Whole exome sequencing revealed a novel homozygous frameshift variant p.Val242GlufsTer52 in the TSPY-like 1 gene TSPYL1. The truncated TSPYL1 protein that lacks the nucleosome assembly protein (NAP) domain was retained in the Golgi of fibroblasts from the three patients while control fibroblasts express full length TSPYL1 in the nucleus. Proteomic analysis of nuclear extracts from fibroblasts identified 24 up- and 20 down-regulated proteins in the patients compared to five controls with 'regulation of cell cycle' as the highest scored biological pathway affected. TSPYL1 deficient cells had prolonged S and G2 phases with reduced cellular proliferation rates. Tspyl1 depletion in zebrafish mimicked the patients' phenotype with early lethality, defects in neurogenesis and cardiac dilation. In conclusion, this study reports the third pedigree with recessive TSPYL1 variants, confirming that TSPYL1 deficiency leads to a combined nervous and reproductive systems disease, and provides for the first time insights into the disease mechanism.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping