Autosomal recessive primary microcephaly (MCPH): a review of clinical, molecular, and evolutionary findings
C Geoffrey Woods1, Jacquelyn Bond, Wolfgang Enard
1Department of Medical Genetics, Cambridge Institute for Medical Research, Cambridge, United Kingdom. cw347@cam.ac.uk
Abstract:
Autosomal recessive primary microcephaly (MCPH) is a neurodevelopmental disorder. It is characterized by two principal features, microcephaly present at birth and nonprogressive mental retardation. The microcephaly is the consequence of a small but architecturally normal brain, and it is the cerebral cortex that shows the greatest size reduction. There are at least seven MCPH loci, and four of the genes have been identified: MCPH1, encoding Microcephalin; MCPH3, encoding CDK5RAP2; MCPH5, encoding ASPM; and MCPH6, encoding CENPJ. These findings are starting to have an impact on the clinical management of families affected with MCPH. Present data suggest that MCPH is the consequence of deficient neurogenesis within the neurogenic epithelium. Evolutionary interest in MCPH has been sparked by the suggestion that changes in the MCPH genes might also be responsible for the increase in brain size during human evolution. Indeed, evolutionary analyses of Microcephalin and ASPM reveal evidence for positive selection during human and great ape evolution. So an understanding of this rare genetic disorder may offer us significant insights into neurogenic mitosis and the evolution of the most striking differences between us and our closest living relatives: brain size and cognitive ability.
Insights
Autosomal recessive primary microcephaly (MCPH) is a rare neurodevelopmental disorder causing small brain size. Genes linked to MCPH may also explain human brain evolution and cognitive differences.
Area of Science:
- Genetics
- Neurodevelopmental Biology
- Evolutionary Biology
Background:
- Autosomal recessive primary microcephaly (MCPH) is a neurodevelopmental disorder characterized by congenital microcephaly and nonprogressive mental retardation.
- The condition results in a small brain, with the cerebral cortex showing the most significant size reduction.
- Several genes (MCPH1, MCPH3, MCPH5, MCPH6) have been identified, offering insights into clinical management.
Purpose of the Study:
- To investigate the genetic basis of Autosomal Recessive Primary Microcephaly (MCPH).
- To explore the role of MCPH genes in neurogenesis and brain size evolution.
- To understand the implications of MCPH for human cognitive evolution.
Main Methods:
- Identification and characterization of genes associated with MCPH.
- Analysis of neurogenesis in affected individuals.
- Evolutionary analyses of MCPH genes (Microcephalin and ASPM).
Main Results:
- Four genes (MCPH1, CDK5RAP2, ASPM, CENPJ) have been identified as causative for MCPH.
- Evidence suggests MCPH results from deficient neurogenesis.
- Evolutionary analyses show positive selection in Microcephalin and ASPM during human and ape evolution.
Conclusions:
- Understanding MCPH provides insights into neurogenic mitosis.
- MCPH genes may have played a role in the evolution of human brain size and cognitive abilities.
- This research connects a rare genetic disorder to fundamental questions in human evolution.
