Unravelling the disease mechanism for TSPYL1 deficiency.
Hum Mol Genet
; 29(20): 3431-3442, 2020 12 18.
Article
in En
| MEDLINE
| ID: mdl-33075815
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 domain was retained in the Golgi of fibroblasts from the three patients, whereas control fibroblasts express full-length TSPYL1 in the nucleus. Proteomic analysis of nuclear extracts from fibroblasts identified 24 upregulated and 20 downregulated proteins in the patients compared with 5 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.
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Sudden Infant Death
/
Nuclear Proteins
/
Frameshift Mutation
/
Proteome
/
Fibroblasts
Type of study:
Prognostic_studies
Limits:
Animals
/
Female
/
Humans
/
Infant
/
Male
/
Newborn
Language:
En
Journal:
Hum Mol Genet
Journal subject:
BIOLOGIA MOLECULAR
/
GENETICA MEDICA
Year:
2020
Document type:
Article
Affiliation country:
Belgium