title: 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.
authors.affiliation: Institut für Humangenetik, Charité - Universitätsmedizin Berlin, Germany.
authors.forename: Marc
authors.initials: M
authors.lastname: Trimborn
authors.forename: Reyk
authors.initials: R
authors.lastname: Richter
authors.forename: Nadine
authors.initials: N
authors.lastname: Sternberg
authors.forename: Ioannis
authors.initials: I
authors.lastname: Gavvovidis
authors.forename: Detlev
authors.initials: D
authors.lastname: Schindler
authors.forename: Andrew P
authors.initials: AP
authors.lastname: Jackson
authors.forename: Eva-Christina
authors.initials: EC
authors.lastname: Prott
authors.forename: Karl
authors.initials: K
authors.lastname: Sperling
authors.forename: Gabriele
authors.initials: G
authors.lastname: Gillessen-Kaesbach
authors.forename: Heidemarie
authors.initials: H
authors.lastname: Neitzel
mesh_terms: D000595:Amino Acid Sequence; D018797:Cell Cycle Proteins; D002478:Cells, Cultured; D002648:Child; D002875:Chromosomes / Q000648:ultrastructure; D003598:Cytoskeletal Proteins; D004252:DNA Mutational Analysis; D006801:Humans; D008607:Intellectual Disability / Q000235:genetics; D008297:Male; D008831:Microcephaly / Q000175:diagnosis* / Q000235:genetics* / Q000473:pathology; D008969:Molecular Sequence Data; D020125:Mutation, Missense; D009419:Nerve Tissue Proteins / Q000235:genetics*; D010641:Phenotype; D016415:Sequence Alignment; D013601:T-Lymphocytes / Q000473:pathology; D044465:White People / Q000208:ethnology
chemical_list: D018797:Cell Cycle Proteins; D003598:Cytoskeletal Proteins; C460645:MCPH1 protein, human; D009419:Nerve Tissue Proteins