Functional studies in yeast confirm the pathogenicity of a new GINS3 Meier-Gorlin syndrome variant.
Clin Genet
; 106(3): 342-346, 2024 Sep.
Article
in En
| MEDLINE
| ID: mdl-38773883
ABSTRACT
Meier-Gorlin syndrome (MGORS) is an autosomal recessive disorder characterized by short stature, microtia, and patellar hypoplasia, and is caused by pathogenic variants of cellular factors involved in the initiation of DNA replication. We previously reported that biallelic variants in GINS3 leading to amino acid changes at position 24 (p.Asp24) cause MGORS. Here, we describe the phenotype of a new individual homozygous for the Asp24Asn variant. We also report the clinical characteristics of an individual harboring a novel homozygous GINS3 variant (Ile25Phe) and features suggestive of MGORS. Modification of the corresponding residue in yeast Psf3 (Val9Phe) compromised S phase progression compared to a humanized Psf3 Val9Ile variant. Expression of Psf3 Val9Phe in yeast also caused sensitivity to elevated temperature and the replicative stress-inducing drug hydroxyurea, confirming partial loss of function of this variant in vivo and allowing us to upgrade the classification of this variant. Taken together, these data validate the critical importance of the GINS DNA replication complex in the molecular etiology of MGORS.
Key words
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Patella
/
Congenital Microtia
/
Growth Disorders
Limits:
Child
/
Female
/
Humans
/
Male
Language:
En
Journal:
Clin Genet
Year:
2024
Document type:
Article
Affiliation country:
Canada
Country of publication:
Denmark