Article

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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    • "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.
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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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    • "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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