These findings reveal several cellular defects in cells carrying the PHC1 mutation and highlight the role of chromatin remodeling in the pathogenesis of PM.
Microcephalin 1 (MCPH1) gene, initially identified as an hTERT repressor, result in two autosomal recessive disorders: primary microcephaly and premature chromosome condensation syndrome.
Microcephalin (MCPH1) and Abnormal spindle-like microcephaly associated (ASPM) are genes mutated in primary microcephaly, a human neurodevelopmental disorder.
We previously mapped the MCPH1 locus, for primary microcephaly, to chromosome 8p23, and here we report that a gene within this interval, encoding a BRCA1 C-terminal domain-containing protein, is mutated in MCPH1 families sharing an ancestral 8p23 haplotype.
We thus expand the clinical spectrum of ASPM mutations by showing that they can occur in patients with seizures and that the history of seizures alone should not necessarily preclude the diagnosis of primary microcephaly.
Our observation adds to the mutation spectrum of ASPM in primary microcephaly, and is to our knowledge the second example of a constitutional, reciprocal translocation responsible for a bona fide autosomal recessive phenotype.
In addition, using patient-specific induced pluripotent stem cells (iPSCs) with dysfunction of the Aspm gene from a primary microcephaly patient, we demonstrate neurogenesis defects result in defective neuronal activity in patient organoids, suggesting a new strategy to study human developmental diseases in central nerve system.
Haplotype analysis using microsatellite markers around the MCPH1-7 and PNKP loci in an Italian family with two sons with primary microcephaly, revealed possible linkage to the MCPH3 locus.
Next generation sequencing analysis of a 6 year old female with primary microcephaly identified novel compound heterozygous mutations (c.524_528del and c.4005-1G>A) in the CDK5RAP2 gene.
Despite being known as MCPH linked gene for more than a decade, the phenotypic spectrum of CDK5RAP2 mutations is still under explored as only eleven families have been reported worldwide.
These findings reveal that RTTN contributes to building full-length centrioles and illuminate the molecular mechanism through which the RTTN (A578P) mutation causes primary microcephaly.Mutations in many centriolar protein-encoding genes cause primary microcephaly.