CENPJ – Autosomal Recessive Primary Microcephaly

Autosomal recessive primary microcephaly (MCPH) is a congenital neurodevelopmental disorder defined by a reduced head circumference at birth and non-progressive intellectual disability. MCPH results from impaired neuronal precursor proliferation leading to diminished cortical neuron numbers in an architecturally normal brain (PMID:25951892).

CENPJ (centromere protein J), also known as CPAP, was mapped to the MCPH6 locus on chromosome 13q12.12-q12.13 in a single consanguineous Pashtoon family. Sequence analysis revealed a homozygous four-base deletion in exon 11, predicted to truncate the protein and disrupt centrosomal function (PMID:16900296).

Inheritance is autosomal recessive with no additional segregating relatives beyond the index family. The only molecular lesion reported is a protein-truncating variant c.3275dup (p.Tyr1092Ter) observed in homozygosity in affected siblings, consistent with loss-of-function as the pathogenic mechanism (PMID:16900296).

Functional assays define CPAP as essential for centriole biogenesis. Truncation of its microtubule-destabilizing domain within amino acids 311–422 abrogates both tubulin-binding and microtubule-destabilizing activities in vitro, implicating disrupted spindle dynamics in MCPH pathogenesis (PMID:18586240).

CPAP is also required for ciliogenesis in neuronal cells: CPAP depletion inhibits cilia formation, and this phenotype is rescued by wild-type but not by an MDD mutant (KR377EE), demonstrating that intrinsic tubulin-dimer binding is critical for centrosome-mediated cilia assembly (PMID:23213448).

Disease-associated missense variants further corroborate pathogenicity. The E1235V mutation impairs centriole elongation, spindle orientation and leads to p53-dependent neuronal apoptosis in hiPSC-derived brain organoids, faithfully recapitulating the MCPH phenotype (PMID:35309908; PMID:37823337).

Modifier analyses reveal that heterozygous variants in CEP63, WDR62, RAD50 and PCNT can exacerbate phenotypic severity in CENPJ-mutant backgrounds, indicating allelic and locus interplay in neural precursor proliferation and informing genetic counseling strategies (PMID:34068194).

In summary, homozygous truncating variants in CENPJ cause autosomal recessive primary microcephaly through CPAP loss-of-function, impairing centriole dynamics and ciliogenesis. Although genetic evidence is limited to a single family, multiple concordant functional studies provide moderate mechanistic support. Key take-home: CENPJ testing has direct clinical utility for diagnosis and genetic counseling in MCPH.

References

• Journal of human genetics • 2006 • A novel deletion mutation in CENPJ gene in a Pakistani family with autosomal recessive primary microcephaly. PMID:16900296
• Experimental cell research • 2008 • Functional characterization of the microtubule-binding and -destabilizing domains of CPAP and d-SAS-4. PMID:18586240
• Biology open • 2012 • CPAP is required for cilia formation in neuronal cells. PMID:23213448
• Genes • 2021 • Modifier Genes in Microcephaly: A Report on WDR62, CEP63, RAD50 and PCNT Variants Exacerbating Disease Caused by Biallelic Mutations of ASPM and CENPJ. PMID:34068194
• Frontiers in cell and developmental biology • 2022 • Modeling Human Primary Microcephaly With hiPSC-Derived Brain Organoids Carrying CPAP-E1235V Disease-Associated Mutant Protein. PMID:35309908
• Journal of cell science • 2023 • Separation-of-function MCPH-associated mutations in CPAP affect centriole number and length. PMID:37823337

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