The first missense alteration in the MCPH1 gene causes autosomal recessive microcephaly with an extremely mild cellular and clinical phenotype

Abstract

Autosomal recessive primary microcephaly (MCPH) is a rare neurodevelopmental disorder characterized by mental retardation and congenital microcephaly with a head circumference at least 4 SD below age and sex means, in the absence of other significant malformations or neurological deficits. Truncating alterations in the MCPH1 gene have previously been shown to exhibit a distinct cellular phenotype, with a high proportion of prophase-like cells (>10%) due to premature chromosome condensation in early G2-and delayed decondensation in early G1-phase of the cell cycle. We report here the first patient with a homozygous substitution of a highly conserved threonine residue by an arginine (c.80C>G, Thr27Arg) localized in the N-terminal BRCT domain of MCPH1. The cellular and clinical phenotype of this patient is much less pronounced than that of previously described patients with truncating alterations in the MCPH1 gene. Firstly, the fraction of prophase-like cells accounts for just 3-4% of the cell population. Secondly, clinically, he has only a very mild mental retardation with predominantly delayed motor skills but normal verbal IQ attainment. Additionally, head circumference was less severely affected, being -2.4 SD at birth and -3 SD at the age of six years. This justifies reconsideration and widening of the clinical phenotype definition of MCPH1.

Exome sequencing identifies recessive CDK5RAP2 variants in patients with isolated agenesis of corpus callosum

“…4,[12][13][14][15][16] In parallel, it was shown that other MCPH patients with mutations in ASPM (MCPH5) or WDR62 (MCPH2) can also exhibit ACC and that a patient with microcephaly harboring a missense in the Microcephalin gene (MCPH1) presented a less severe clinical phenotype compared with the patients with truncating mutations in the same gene. [17][18][19] We might therefore propose that mutations completely abolishing CDK5RAP2 protein function, such as nonsense or frameshift mutations, would lead to a microcephaly phenotype, whereas recessive missense mutations, where there may be some residual function, might result in a different phenotype such as isolated ACC. This is the first time that recessive missense mutations in CDK5RAP2 are specifically associated with corpus callosum anomalies, a finding which provides new avenues to a better understanding of the role of the centrosome into early development of corpus callosum.…”

MCPH1 Functions in an H2AX-dependent but MDC1-independent Pathway in Response to DNA Damage

“…3B). A recent report describes a missense mutation in the N-BRCT domain that changes a conserved Thr to Arg (T27R) in the BRCT domain (26). What is interesting is that the patient had a mild clinical and cellular phenotype compared with known mutant alleles of MCPH1 that are truncating mutations.…”

Misregulation of mitotic chromosome segregation in a new type of autosomal recessive primary microcephaly

“…We also did not observe any defect in the process of chromosome condensation comparable to the cellular phenotype caused by MCPH1 mutations. 25,33 The cell cycle progression and the spindle checkpoint activity in MCPH8 patient cells was analyzed by FACS on both lymphoblastoid cells and PHA stimulated T-lymphocytes. Cells were arrested in mitosis for 12 h with nocodazole, a microtubule-depolymerizing agent and subsequently released from mitosis during either 30 min or 2 h. Mitotic indices and DNA profiles were evaluated in order to detect the response of cells to metaphase arrest caused by nocodazole.…”