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SHP2's gain-of-function in Werner syndrome causes childhood disease onset likely resulting from negative genetic interaction.

Authors :
Priolo M
Palermo V
Aiello F
Ciolfi A
Pannone L
Muto V
Motta M
Mancini C
Radio FC
Niceta M
Leoni C
Pintomalli L
Carrozzo R
Rajola G
Mammì C
Zampino G
Martinelli S
Dallapiccola B
Pichierri P
Tartaglia M
Source :
Clinical genetics [Clin Genet] 2022 Jul; Vol. 102 (1), pp. 12-21. Date of Electronic Publication: 2022 Apr 17.
Publication Year :
2022

Abstract

Prompt diagnosis of complex phenotypes is a challenging task in clinical genetics. Whole exome sequencing has proved to be effective in solving such conditions. Here, we report on an unpredictable presentation of Werner Syndrome (WRNS) in a 12-year-old girl carrying a homozygous truncating variant in RECQL2, the gene mutated in WRNS, and a de novo activating missense change in PTPN11, the major Noonan syndrome gene, encoding SHP2, a protein tyrosine phosphatase positively controlling RAS function and MAPK signaling, which have tightly been associated with senescence in primary cells. All the major WRNS clinical criteria were present with an extreme precocious onset and were associated with mild intellectual disability, severe growth retardation and facial dysmorphism. Compared to primary fibroblasts from adult subjects with WRNS, proband's fibroblasts showed a dramatically reduced proliferation rate and competence, and a more accelerated senescence, in line with the anticipated WRNS features occurring in the child. In vitro functional characterization of the SHP2 mutant documented its hyperactive behavior and a significantly enhanced activation of the MAPK pathway. Based on the functional interaction of WRN and MAPK signaling in processes relevant to replicative senescence, these findings disclose a unique phenotype likely resulting from negative genetic interaction.<br /> (© 2022 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Details

Language :
English
ISSN :
1399-0004
Volume :
102
Issue :
1
Database :
MEDLINE
Journal :
Clinical genetics
Publication Type :
Academic Journal
Accession number :
35396703
Full Text :
https://doi.org/10.1111/cge.14140