Novel PCNT variants in MOPDII with attenuated growth restriction and pachygyria
Stephanie Waich1,2, Andreas R Janecke1,3, Walther Parson4,5
1Department of Pediatrics I, Medical University of Innsbruck, Innsbruck, Austria.
Abstract:
Biallelic loss-of-function mutations in the centrosomal pericentrin gene (PCNT) cause microcephalic osteodysplastic primordial dwarfism type II (MOPDII), which is characterized by extreme growth retardation, microcephaly, skeletal dysplasia, and dental anomalies. Life expectancy is reduced due to a high risk of cerebral vascular anomalies. Here, we report two siblings with MOPDII and attenuated growth restriction, and pachygyria. Compound heterozygosity for two novel truncated PCNT variants was identified. Both truncated PCNT proteins were expressed in patient's fibroblasts, with a reduced total protein amount compared to control. Patient's fibroblasts showed impaired cell cycle progression. As a novel finding, 20% of patient's fibroblasts were shown to express PCNT comparable to control. This was associated with normal mitotic morphology and normal co-localization of mutated PCNT with centrosome-associated proteins γ-tubulin and centrin 3, suggesting some residual function of truncated PCNT proteins. These data expand the clinical and molecular spectrum of MOPDII and indicate that residual PCNT function might be associated with attenuated growth restriction in MOPDII.
Insights
Biallelic loss-of-function mutations in the pericentrin gene (PCNT) cause MOPDII. Novel truncated PCNT variants in siblings with attenuated growth restriction suggest residual PCNT function may influence MOPDII severity.
Area of Science:
- Genetics
- Cell Biology
- Developmental Biology
Background:
- Microcephalic osteodysplastic primordial dwarfism type II (MOPDII) is a severe genetic disorder caused by mutations in the PCNT gene.
- MOPDII is characterized by extreme growth retardation, microcephaly, skeletal dysplasia, and reduced life expectancy due to cerebrovascular issues.
Purpose of the Study:
- To investigate the clinical and molecular spectrum of MOPDII.
- To analyze the functional impact of novel PCNT variants in patients with attenuated MOPDII phenotypes.
Main Methods:
- Genetic sequencing to identify PCNT variants.
- Fibroblast culture and protein expression analysis.
- Cell cycle progression and centrosome localization studies.
Main Results:
- Identified compound heterozygous, novel truncated PCNT variants in two siblings with MOPDII and attenuated growth restriction.
- Truncated PCNT proteins were expressed in patient fibroblasts, with reduced total protein levels and impaired cell cycle progression.
- A subset of patient fibroblasts showed normal PCNT expression, mitotic morphology, and centrosome protein co-localization, indicating residual PCNT function.
Conclusions:
- These findings expand the known clinical and molecular spectrum of MOPDII.
- Residual function of truncated PCNT proteins may correlate with attenuated growth restriction in MOPDII patients.
