RGD Reference Report - Kinetochore KMN network gene CASC5 mutated in primary microcephaly. - Rat Genome Database

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Kinetochore KMN network gene CASC5 mutated in primary microcephaly.

Authors: Genin, A  Desir, J  Lambert, N  Biervliet, M  Van Der Aa, N  Pierquin, G  Killian, A  Tosi, M  Urbina, M  Lefort, A  Libert, F  Pirson, I  Abramowicz, M 
Citation: Genin A, etal., Hum Mol Genet. 2012 Dec 15;21(24):5306-17. doi: 10.1093/hmg/dds386. Epub 2012 Sep 13.
RGD ID: 9685043
Pubmed: PMID:22983954   (View Abstract at PubMed)
DOI: DOI:10.1093/hmg/dds386   (Journal Full-text)

Several genes expressed at the centrosome or spindle pole have been reported to underlie autosomal recessive primary microcephaly (MCPH), a neurodevelopmental disorder consisting of an important brain size reduction present since birth, associated with mild-to-moderate mental handicap and no other neurological feature nor associated malformation. Here, we report a mutation of CASC5 (aka Blinkin, or KNL1, or hSPC105) in MCPH patients from three consanguineous families, in one of which we initially reported the MCPH4 locus. The combined logarithm of odds score of the three families was >6. All patients shared a very rare homozygous mutation of CASC5. The mutation induced skipping of exon 18 with subsequent frameshift and truncation of the predicted protein. CASC5 is part of the KMN network of the kinetochore and is required for proper microtubule attachment to the chromosome centromere and for spindle-assembly checkpoint (SAC) activation during mitosis. Like MCPH gene ASPM, CASC5 is upregulated in the ventricular zone (VZ) of the human fetal brain. CASC5 binds BUB1, BUBR1, ZWINT-1 and interestingly it binds to MIS12 through a protein domain which is truncated by the mutation. CASC5 localized at the equatorial plate like ZWINT-1 and BUBR1, while ASPM, CEP152 and PCTN localized at the spindle poles in our patients and in controls. Comparison of primate and rodent lineages indicates accelerated evolution of CASC5 in the human lineage. Our data provide strong evidence for CASC5 as a novel MCPH gene, and underscore the role of kinetochore integrity in proper volumetric development of the human brain.

RGD Manual Disease Annotations    Click to see Annotation Detail View
TermQualifierEvidenceWithReferenceNotesSourceOriginal Reference(s)
primary autosomal recessive microcephaly  IAGP 9685043DNA:mutation:cds: c.6125 G>A and p. M2041I(human)RGD 
primary autosomal recessive microcephaly  ISOKNL1 (Homo sapiens)9685043; 9685043DNA:mutation:cds: c.6125 G>A and p. M2041I(human)RGD 

Objects Annotated

Genes (Rattus norvegicus)
Knl1  (kinetochore scaffold 1)

Genes (Mus musculus)
Knl1  (kinetochore scaffold 1)

Genes (Homo sapiens)
KNL1  (kinetochore scaffold 1)


Additional Information