A Third Novel Locus for Primary Autosomal Recessive Microcephaly Maps to Chromosome 9q34

Molecular Medicine Unit, St. James's University Hospital, Leeds, United Kingdom.
The American Journal of Human Genetics (Impact Factor: 10.93). 02/2000; 66(2):724-7. DOI: 10.1086/302777
Source: PubMed


Primary autosomal recessive microcephaly is a clinical diagnosis of exclusion in an individual with a head circumference >/=4 SDs below the expected age-and-sex mean. There is associated moderate mental retardation, and neuroimaging shows a small but structurally normal cerebral cortex. The inheritance pattern in the majority of cases is considered to be autosomal recessive. Although genetic heterogeneity for this clinical phenotype had been expected, this has only recently been demonstrated, with the mapping of two loci for autosomal recessive primary microcephaly: MCPH1 at 8p and MCPH2 at 19q. We have studied a large multiaffected consanguineous pedigree, using a whole-genome search, and have identified a third locus, MCPH3 at 9q34. The minimal critical region is approximately 12 cM, being defined by the markers cen-D9S1872-D9S159-tel, with a maximum two-point LOD score of 3.76 (recombination fraction 0) observed for the marker D9S290.

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    • "Gene Locus Gene product References (gene and/or locus) OMIM MCPH1 MICROCEPHALIN MCPH1 MICROCEPHALIN [40] 6 0 7 1 1 7 WDR62 (WD repeat-containing protein 62) MCPH2 WDR62 [169] 6 1 3 5 8 3 CDK5RAP2 (CDK5 regulatory subunit-associated protein 2) MCPH3 CDK5RAP2 [170] 6 0 8 2 0 1 CASC5 (cancer susceptibility candidate 5) MCPH4 CASC5 [171] "
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    ABSTRACT: Autosomal recessive primary microcephaly (MCPH) is a rare hereditary neurodevelopmental disorder characterized by a marked reduction in brain size and intellectual disability. MCPH is genetically heterogeneous and can exhibit additional clinical features that overlap with related disorders including Seckel syndrome, Meier-Gorlin syndrome, and microcephalic osteodysplastic dwarfism. In this review, we discuss the key proteins mutated in MCPH. To date, MCPH-causing mutations have been identified in twelve different genes, many of which encode proteins that are involved in cell cycle regulation or are present at the centrosome, an organelle crucial for mitotic spindle assembly and cell division. We highlight recent findings on MCPH proteins with regard to their role in cell cycle progression, centrosome function, and early brain development.
    BioMed Research International 12/2014; 2014:547986. DOI:10.1155/2014/547986 · 1.58 Impact Factor
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    • "Further tests did not reveal any significant hearing impairment or epilepsy as a cause for the speech deficit. Therefore, although sensorineural hearing loss has been reported in two patients with mutations in CDK5RAP2[5,15], this is not a consistent finding in MCPH3. Both patients had microcephaly, simplified gyral pattern of the cerebral cortex, with shallow sulci anteriorly and deep sulci parietally and posteriorly, and corpus callosum hypogensis on cMRI. "
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    ABSTRACT: Background Primary autosomal recessive microcephaly (MCPH) is a rare neurodevelopmental disorder that results in severe microcephaly at birth with pronounced reduction in brain volume, particularly of the neocortex, simplified cortical gyration and intellectual disability. Homozygous mutations in the Cyclin-dependent kinase 5 regulatory subunit-associated protein 2 gene CDK5RAP2 are the cause of MCPH3. Despite considerable interest in MCPH as a model disorder for brain development, the underlying pathomechanism has not been definitively established and only four pedigrees with three CDK5RAP2 mutations have been reported. Specifically for MCPH3, no detailed radiological or histological descriptions exist. Methods/Results We sought to characterize the clinical and radiological features and pathological cellular processes that contribute to the human MCPH3 phenotype. 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. Sequencing of the coding exons and exon/intron splice junctions of the CDK5RAP2 gene identified homozygosity for the novel nonsense mutation, c.4441C > T (p.Arg1481*), in both affected sons. cMRI showed microcephaly, simplified gyral pattern and hypogenesis of the corpus callosum. The cellular phenotype was assessed in EBV-transformed lymphocyte cell lines established from the two affected sons and compared with healthy male controls. CDK5RAP2 protein levels were below detection level in immortalized lymphocytes from the patients. Moreover, mitotic spindle defects and disrupted γ-tubulin localization to the centrosome were apparent. Conclusion These results suggest that spindle defects and a disruption of centrosome integrity play an important role in the development of microcephaly in MCPH3.
    Orphanet Journal of Rare Diseases 04/2013; 8(1):59. DOI:10.1186/1750-1172-8-59 · 3.36 Impact Factor
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    • "The fact that MCPH is detectable during fetal development, is nonprogressive, and has a major effect on the cortex suggests that it manifests itself through a deficiency in proliferation of cortical neural progenitor cells. MCPH has been linked to eight genetic loci and five known genes (Jackson et al., 1998; Jamieson et al., 2000, 1999; Kumar et al., 2009; Leal et al., 2003; Moynihan et al., 2000; Pattison et al., 2000; Roberts et al., 1999). All of these play a role in centrosome-associated functions (Cox et al., 2006; Fong et al., 2008; Pfaff et al., 2007). "
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    ABSTRACT: Primary autosomal-recessive microcephaly (MCPH) and Majewski osteodysplastic primordial dwarfism type II (MOPDII) are both genetic diseases that result in decreased brain size at birth. MCPH is thought to arise from alterations in the size of the neural progenitor pool, but the cause of this defect has not been thoroughly explored. We find that one of the genes associated with MCPH, Cdk5rap2, is highly expressed in the neural progenitor pool and that its loss results in a depletion of apical progenitors and increased cell-cycle exit leading to premature neuronal differentiation. We link Cdk5rap2 function to the pericentriolar material protein pericentrin, loss of function of which is associated with MOPDII. Depletion of pericentrin in neural progenitors phenocopies effects of Cdk5rap2 knockdown and results in decreased recruitment of Cdk5rap2 to the centrosome. Our findings uncover a common mechanism, involving aberrations in the neurogenesis program, that may underlie the development of microcephaly in multiple diseases.
    Neuron 05/2010; 66(3):386-402. DOI:10.1016/j.neuron.2010.03.036 · 15.05 Impact Factor
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