PCNT – Microcephalic Osteodysplastic Primordial Dwarfism Type II

Microcephalic osteodysplastic primordial dwarfism type II (MOPD II) is an autosomal recessive syndrome marked by severe intrauterine and postnatal growth restriction, extreme short stature (<100 cm), profound microcephaly, skeletal dysplasia, dental anomalies, and a high risk of cerebrovascular complications including intracranial aneurysms and moyamoya disease. Biallelic pathogenic variants in the pericentrin gene (PCNT; HGNC:16068) underlie MOPD II, disrupting centrosome integrity and cell cycle progression.

Genetic evidence for PCNT involvement derives from both isolated case reports and a large multi-family cohort. A Colombian patient was found homozygous for c.1468C>T (p.Gln490Ter) ([PMID:24928221]), and a European misdiagnosed series highlighted vascular complications leading to the correct identification of PCNT mutations in adults with subarachnoid hemorrhage ([PMID:24973050]). In a landmark study of 24 Seckel/MOPD II families, 28 patients from 24 unrelated families harbored 13 distinct loss-of-function variants—including nonsense, frameshift, splice, and a cryptic splice missense event—each segregating with disease in consanguineous pedigrees ([PMID:19643772]).

The variant spectrum in MOPD II is dominated by truncating alleles: 15 frameshift and 10 nonsense mutations, two canonical splice-site disruptions, and one founder splicing variant c.3465-1G>A in the Druze population ([PMID:30922925]). Recurrent and private alleles have been identified across diverse ethnic groups, with no reported hypomorphic or deep-intronic variants to date. A representative pathogenic allele is c.1468C>T (p.Gln490Ter).

Functional assays corroborate a loss-of-function mechanism: patient fibroblasts expressing truncated PCNT exhibit impaired centrosomal localization, defective mitotic spindle organization, and delayed cell cycle progression ([PMID:32557621]). In Pcnt–/– mouse models, vascular anomalies including intracranial hemorrhage recapitulate human cerebrovascular phenotypes ([PMID:30413633]). In vitro expression studies further demonstrate that C-terminal truncations abrogate PCNT secretion and stability ([PMID:9573015]).

No studies have formally disputed the PCNT–MOPD II association. The integration of robust segregation data, a consistent loss-of-function variant spectrum, and concordant cellular and animal models supports a definitive gene–disease relationship.

Key Take-home: PCNT genetic testing is diagnostic for MOPD II, guiding early vascular surveillance and personalized management of skeletal and neurological complications.

References

• Journal of medical case reports • 2014 • A new mutation of the PCNT gene in a Colombian patient with microcephalic osteodysplastic primordial dwarfism type II: a case report. PMID:24928221
• Journal of medical genetics • 2010 • Molecular analysis of pericentrin gene (PCNT) in a series of 24 Seckel/microcephalic osteodysplastic primordial dwarfism type II (MOPD II) families. PMID:19643772
• Clinical genetics • 2020 • Novel PCNT variants in MOPDII with attenuated growth restriction and pachygyria. PMID:32557621
• Neurology • 2018 • PCNT point mutations and familial intracranial aneurysms. PMID:30413633
• Blood • 1998 • The carboxyl-terminal region of protein C is essential for its secretion. PMID:9573015

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