The molecular landscape of ASPM mutations in primary microcephaly

Abstract

Background: Autosomal recessive primary microcephaly (MCPH) is a model disease to study human neurogenesis. In affected individuals the brain grows at a reduced rate during fetal life resulting in a small but structurally normal brain and mental retardation. The condition is genetically heterogeneous with mutations in ASPM being most commonly reported. Methods and results: We have examined this further by studying three cohorts of microcephalic children to extend both the phenotype and the mutation spectrum. Firstly, in 99 consecutively ascertained consanguineous families with a strict diagnosis of MCPH, 41 (41%) were homozygous at the MCPH5 locus and all but two families had mutations. Thus, 39% of consanguineous MCPH families had homozygous ASPM mutations. Secondly, in 27 non-consanguineous, predominantly Caucasian families with a strict diagnosis of MCPH, 11 (40%) had ASPM mutations. Thirdly, in 45 families with a less restricted phenotype including microcephaly and mental retardation, but regardless of other neurological features, only 3 (7%) had an ASPM mutation. This report contains 27 novel mutations and almost doubles the number of MCPH associated ASPM mutations known to 57. All but one of the mutations lead to the use of a premature termination codon, 23 were nonsense mutations, 28 deletions or insertions, 5 splicing, and 1 was a translocation. Seventeen of the 57 mutations were recurrent. There were no definitive missense mutations found nor was there any mutation/phenotype correlation. ASPM mutations were found in all ethnic groups studied. Conclusion: This study confirms that mutations in ASPM are the most common cause of MCPH, that ASPM mutations are restricted to individuals with an MCPH phenotype, and that ASPM testing in primary microcephaly is clinically useful.Our most defining feature as a species is our brain with its large size and cognitive functions leading to our great adaptability.

Mutations in mouse Aspm (abnormal spindle-like microcephaly associated) cause not only microcephaly but also major defects in the germline

“…ASPM mutations identified in microcephaly patients typically lead to protein truncation, with no correlation between the severity of the disorder and the length of the truncated protein (14,15). This is consistent with the notion that the lack of the C-terminal domain of ASPM, which mediates midbody localization (13), may be sufficient to cause microcephaly in humans.…”

“…S1A). In this context, it is worth noting that all ASPM mutations identified in human microcephaly patients (with the exception of a missense mutation) truncate the protein in, or before, the region encoded by exon 26 (15,23).…”

Citron kinase – renaissance of a neglected mitotic kinase

“…Some of the mutations identified in the kinase domain abolish the kinase activity of CIT-K in vitro (Li et al, 2016), clearly indicating that the kinase activity is essential for brain development and cytokinesis. The CIT-K-binding partner ASPM is one of the most frequently mutated genes in autosomal-recessive human microcephaly and one of the main determinants of human brain size (Nicholas et al, 2009), suggesting that a common cellular mechanism underlies the cause of primary microcephaly. The presence of multinucleated neurons in patients carrying CIT mutations (Harding et al, 2016;Li et al, 2016) and the established roles for both CIT-K and ASPM in cytokinesis (Higgins et al, 2010;Paramasivam et al, 2007) suggest that cytokinesis failure and, consequently, apoptosis is one such possible mechanism.…”

A Molecular Genetic Study of Autosomal Recessive Primary Microcephaly in three Pakistani Kindred

“…The most common and frequent sites of mutations are found throughout ASPM gene and uptill now there are total 57 ASPM mutations recorded ( [10], [19], [21], [22] and [23).…”