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The first missense alteration in the MCPH1 gene causes autosomal recessive microcephaly with an extremely mild cellular and clinical phenotype
Author(s) -
Trimborn Marc,
Richter Reyk,
Sternberg Nadine,
Gavvovidis Ioannis,
Schindler Detlev,
Jackson Andrew P.,
Prott EvaChristina,
Sperling Karl,
GillessenKaesbach Gabriele,
Neitzel Heidemarie
Publication year - 2005
Publication title -
human mutation
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.981
H-Index - 162
eISSN - 1098-1004
pISSN - 1059-7794
DOI - 10.1002/humu.9382
Subject(s) - microcephaly , biology , phenotype , genetics , missense mutation , neurodevelopmental disorder , population , prophase , failure to thrive , gene , medicine , environmental health , meiosis
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 . © 2005 Wiley‐Liss, Inc.