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: 10.99). 02/2000; 66(2):724-7. DOI: 10.1086/302777
Source: PubMed

ABSTRACT 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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Available from: Nicholas Lench, Aug 26, 2015
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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 · 2.71 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 · 15.98 Impact Factor
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    • "To date , all six of the nonsyndromic pri - mary microencephaly disorders in hu - mans have been mapped , and none of their chromosomal locations coincides with the location of human Shc1 at 1q21 ( Huebner et al . , 1994 ; Yulug et al . , 1995 ; Jamieson et al . , 1999 ; Roberts et al . , 1999 ; Moynihan et al . , 2000 ; Jackson et al . , 2002 ; Bond et al . , 2003 ; Leal et al . , 2003 ) . Although four of these disorders are associated with muta - tions in genes ( MCPH1 / Microcephalin ; MCPH3 / CDK5RAP2 ; MCPH5 / ASPM ; MCPH6 / CENPJ ) encoding proteins that are thought to affect the normal progres - sion of the cell cycle in neural progenitors ( J"
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    ABSTRACT: Brain size is precisely regulated during development and involves coordination of neural progenitor cell proliferation, differentiation, and survival. The adapter protein ShcA transmits signals from receptor tyrosine kinases via MAPK (mitogen-activated protein kinase)/ERK (extracellular signal-regulated kinase) and PI3K (phosphatidylinositol 3-kinase)/Akt signaling pathways. In the CNS, ShcA expression is high during embryonic development but diminishes as cells differentiate and switches to ShcB/Sck/Sli and ShcC/N-Shc/Rai. To directly test ShcA function in brain development, we used Cre/lox technology to express a dominant-negative form of ShcA (ShcFFF) in nestin-expressing neural progenitors. ShcFFF-expressing mice display microencephaly with brain weights reduced to 50% of littermate controls throughout postnatal and adult life. The cerebrum appeared most severely affected, but the gross architecture of the brain is normal. Body weight was mildly affected with a delay in reaching mature weight. At a mechanistic level, the ShcFFF microencephaly phenotype appears to be primarily attributable to elevated apoptosis levels throughout the brain from embryonic day 10.5 (E10.5) to E12, which declined by E14.5. Apoptosis remained at normal basal levels throughout postnatal development. Proliferation indices were not significantly altered in the embryonic neuroepithelium or within the postnatal subventricular zone. In another approach with the same nestin-Cre transgene, conditional deletion of ShcA in mice with a homozygous floxed shc1 locus also showed a similar microencephaly phenotype. Together, these data suggest a critical role for ShcA in neural progenitor survival signaling and in regulating brain size.
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