Unravelling the disease mechanism for TSPYL1 deficiency
© The Author(s) 2020. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissionsoup.com..
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.
| Medienart: |
E-Artikel |
|---|
| Erscheinungsjahr: |
2020 |
|---|---|
| Erschienen: |
2020 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:29 |
|---|---|
| Enthalten in: |
Human molecular genetics - 29(2020), 20 vom: 18. Dez., Seite 3431-3442 |
| Sprache: |
Englisch |
|---|
| Beteiligte Personen: |
Buyse, Gunnar [VerfasserIn] |
|---|
| Links: |
|---|
| Themen: |
Journal Article |
|---|
| Anmerkungen: |
Date Completed 30.08.2021 Date Revised 07.12.2022 published: Print Citation Status MEDLINE |
|---|
| doi: |
10.1093/hmg/ddaa233 |
|---|
| funding: |
|
|---|---|
| Förderinstitution / Projekttitel: |
|
| PPN (Katalog-ID): |
NLM316451509 |
|---|
| LEADER | 01000naa a22002652 4500 | ||
|---|---|---|---|
| 001 | NLM316451509 | ||
| 003 | DE-627 | ||
| 005 | 20231225161118.0 | ||
| 007 | cr uuu---uuuuu | ||
| 008 | 231225s2020 xx |||||o 00| ||eng c | ||
| 024 | 7 | |a 10.1093/hmg/ddaa233 |2 doi | |
| 028 | 5 | 2 | |a pubmed24n1054.xml |
| 035 | |a (DE-627)NLM316451509 | ||
| 035 | |a (NLM)33075815 | ||
| 040 | |a DE-627 |b ger |c DE-627 |e rakwb | ||
| 041 | |a eng | ||
| 100 | 1 | |a Buyse, Gunnar |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a Unravelling the disease mechanism for TSPYL1 deficiency |
| 264 | 1 | |c 2020 | |
| 336 | |a Text |b txt |2 rdacontent | ||
| 337 | |a ƒaComputermedien |b c |2 rdamedia | ||
| 338 | |a ƒa Online-Ressource |b cr |2 rdacarrier | ||
| 500 | |a Date Completed 30.08.2021 | ||
| 500 | |a Date Revised 07.12.2022 | ||
| 500 | |a published: Print | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a © The Author(s) 2020. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissionsoup.com. | ||
| 520 | |a 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 | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Research Support, Non-U.S. Gov't | |
| 650 | 7 | |a Nuclear Proteins |2 NLM | |
| 650 | 7 | |a Proteome |2 NLM | |
| 650 | 7 | |a TSPYL1 protein, human |2 NLM | |
| 700 | 1 | |a Di Michele, Michela |e verfasserin |4 aut | |
| 700 | 1 | |a Wijgaerts, Anouck |e verfasserin |4 aut | |
| 700 | 1 | |a Louwette, Sophie |e verfasserin |4 aut | |
| 700 | 1 | |a Wittevrongel, Christine |e verfasserin |4 aut | |
| 700 | 1 | |a Thys, Chantal |e verfasserin |4 aut | |
| 700 | 1 | |a Downes, Kate |e verfasserin |4 aut | |
| 700 | 1 | |a Ceulemans, Berten |e verfasserin |4 aut | |
| 700 | 1 | |a Van Esch, Hild |e verfasserin |4 aut | |
| 700 | 1 | |a Van Geet, Chris |e verfasserin |4 aut | |
| 700 | 1 | |a Freson, Kathleen |e verfasserin |4 aut | |
| 773 | 0 | 8 | |i Enthalten in |t Human molecular genetics |d 1994 |g 29(2020), 20 vom: 18. Dez., Seite 3431-3442 |w (DE-627)NLM012650358 |x 1460-2083 |7 nnns |
| 773 | 1 | 8 | |g volume:29 |g year:2020 |g number:20 |g day:18 |g month:12 |g pages:3431-3442 |
| 856 | 4 | 0 | |u http://dx.doi.org/10.1093/hmg/ddaa233 |3 Volltext |
| 912 | |a GBV_USEFLAG_A | ||
| 912 | |a GBV_NLM | ||
| 951 | |a AR | ||
| 952 | |d 29 |j 2020 |e 20 |b 18 |c 12 |h 3431-3442 | ||