Molecular genetics of human primary microcephaly: an overview

Autosomal recessive primary microcephaly (MCPH) is a neurodevelopmental disorder that is characterised by microcephaly present at birth and non-progressive mental retardation. Microcephaly is the outcome of a smaller but architecturally normal brain; the cerebral cortex exhibits a significant decrease in size. MCPH is a neurogenic mitotic disorder, though affected patients demonstrate normal neuronal migration, neuronal apoptosis and neural function. Twelve MCPH loci (MCPH1-MCPH12) have been mapped to date from various populations around the world and contain the following genes: Microcephalin, WDR62, CDK5RAP2, CASC5, ASPM, CENPJ, STIL, CEP135, CEP152, ZNF335, PHC1 and CDK6. It is predicted that MCPH gene mutations may lead to the disease phenotype due to a disturbed mitotic spindle orientation, premature chromosomal condensation, signalling response as a result of damaged DNA, microtubule dynamics, transcriptional control or a few other hidden centrosomal mechanisms that can regulate the number of neurons produced by neuronal precursor cells. Additional findings have further elucidated the microcephaly aetiology and pathophysiology, which has informed the clinical management of families suffering from MCPH. The provision of molecular diagnosis and genetic counselling may help to decrease the frequency of this disorder.

[1]  N. Tommerup,et al.  Chromosomal breakage, endomitosis, endoreduplication, and hypersensitivity toward radiomimetric and alkylating agents: A possible new autosomal recessive mutation in a girl with craniosynostosis and microcephaly , 1993, Human Genetics.

[2]  D. Schindler,et al.  Abnormal centrosome and spindle morphology in a patient with autosomal recessive primary microcephaly type 2 due to compound heterozygous WDR62 gene mutation , 2013, Orphanet Journal of Rare Diseases.

[3]  Jacqueline K. White,et al.  Mcph1-Deficient Mice Reveal a Role for MCPH1 in Otitis Media , 2013, PloS one.

[4]  D. Glover,et al.  A requirement for the Abnormal Spindle protein to organise microtubules of the central spindle for cytokinesis in Drosophila. , 2002, Journal of cell science.

[5]  Pierre Gressens,et al.  Many roads lead to primary autosomal recessive microcephaly , 2010, Progress in Neurobiology.

[6]  Christopher A. Walsh,et al.  Molecular genetics of human microcephaly , 2001, Current opinion in neurology.

[7]  B. Finlay,et al.  Linked regularities in the development and evolution of mammalian brains. , 1995, Science.

[8]  C. Woods,et al.  What primary microcephaly can tell us about brain growth. , 2006, Trends in molecular medicine.

[9]  P. Rakic.  Specification of cerebral cortical areas. , 1988, Science.

[10]  L. Zon,et al.  The Zebra fish cassiopeia Mutant Reveals that SIL Is Required for Mitotic Spindle Organization , 2007, Molecular and Cellular Biology.

[11]  Anthony A. Hyman,et al.  SAS-4 Is a C. elegans Centriolar Protein that Controls Centrosome Size , 2003, Cell.

[12]  R. Nowakowski,et al.  Cdk5rap2 exposes the centrosomal root of microcephaly syndromes. , 2011, Trends in cell biology.

[13]  M. Mann,et al.  Proteomic characterization of the human centrosome by protein correlation profiling , 2003, Nature.

[14]  R. Saunders,et al.  The Drosophila Gene abnormal spindle Encodes a Novel Microtubule-associated Protein That Associates with the Polar Regions of the Mitotic Spindle , 1997, The Journal of cell biology.

[15]  O. Ninnemann,et al.  What’s the hype about CDK5RAP2? , 2011, Cellular and Molecular Life Sciences.

[16]  Hussain Jafri,et al.  Mutations in microcephalin cause aberrant regulation of chromosome condensation. , 2004, American journal of human genetics.

[17]  D. St Johnston,et al.  From Stem Cell to Embryo without Centrioles , 2007, Current Biology.

[18]  C. Woods,et al.  Primary microcephaly: do all roads lead to Rome? , 2009, Trends in genetics : TIG.

[19]  M. Fichera,et al.  The molecular landscape of ASPM mutations in primary microcephaly , 2008, Journal of Medical Genetics.

[20]  C. Walsh,et al.  Mutations in WDR62, encoding a centrosome-associated protein, cause microcephaly with simplified gyri and abnormal cortical architecture , 2010, Nature Genetics.

[21]  K. Sperling,et al.  The first missense alteration in the MCPH1 gene causes autosomal recessive microcephaly with an extremely mild cellular and clinical phenotype , 2005, Human mutation.

[22]  J. Loturco,et al.  ASPM and Citron Kinase Co-Localize to the Midbody Ring during Cytokinesis , 2007, Cell cycle.

[23]  W. Ahmad,et al.  A novel deletion mutation in CENPJ gene in a Pakistani family with autosomal recessive primary microcephaly , 2006, Journal of Human Genetics.

[24]  Martin S. Taylor,et al.  CEP152 is a genome maintenance protein disrupted in Seckel syndrome , 2011, Nature Genetics.

[25]  D. Kell.  BMC Medical Genomics , 2008 .

[26]  A. Munnich,et al.  Compound heterozygous ASPM mutations associated with microcephaly and simplified cortical gyration in a consanguineous Algerian family. , 2009, European journal of medical genetics.

[27]  P. Hinds,et al.  From Cell Cycle to Differentiation: An Expanding Role for Cdk6 , 2006, Cell cycle.

[28]  C. Woods,et al.  Autosomal recessive primary microcephaly (MCPH): a review of clinical, molecular, and evolutionary findings. , 2005, American journal of human genetics.

[29]  J. Raff,et al.  Flies without Centrioles , 2006, Cell.

[30]  Zhao-Qi Wang,et al.  MCPH1 regulates the neuroprogenitor division mode by coupling the centrosomal cycle with mitotic entry through the Chk1–Cdc25 pathway , 2011, Nature Cell Biology.

[31]  E. Schröck,et al.  Haploinsufficiency of ARID1B, a member of the SWI/SNF-a chromatin-remodeling complex, is a frequent cause of intellectual disability. , 2012, American journal of human genetics.

[32]  M. Kessel,et al.  Geminin Coordinates Cell Cycle and Developmental Control , 2004, Cell cycle.

[33]  C. Walsh,et al.  Microcephaly Gene Links Trithorax and REST/NRSF to Control Neural Stem Cell Proliferation and Differentiation , 2012, Cell.

[34]  S. Blanton,et al.  Mutations in STIL, encoding a pericentriolar and centrosomal protein, cause primary microcephaly. , 2009, American journal of human genetics.

[35]  MANIFESTATIONS OF A RECESSIVE GENE FOR MICROCEPHALY IN A POPULATION ISOLATE. , 1964, Journal de genetique humaine.

[36]  P. Hinds,et al.  cdk6 Can Shorten G1 Phase Dependent upon the N-terminal INK4 Interaction Domain* , 1999, The Journal of Biological Chemistry.

[37]  Vladimir Larionov,et al.  The microcephaly ASPM gene is expressed in proliferating tissues and encodes for a mitotic spindle protein. , 2005, Human molecular genetics.

[38]  A. Noegel,et al.  CDK6 associates with the centrosome during mitosis and is mutated in a large Pakistani family with primary microcephaly. , 2013, Human molecular genetics.

[39]  T. Tang,et al.  Protein 4.1 R-135 Interacts with a Novel Centrosomal Protein (CPAP) Which Is Associated with the γ-Tubulin Complex , 2000, Molecular and Cellular Biology.

[40]  R. Kuriyama,et al.  Characterization of Cep135, a novel coiled-coil centrosomal protein involved in microtubule organization in mammalian cells , 2002, The Journal of cell biology.

[41]  A. Pagnamenta,et al.  A Novel Nonsense CDK5RAP2 Mutation in a Somali Child With Primary Microcephaly and Sensorineural Hearing Loss , 2012, American journal of medical genetics. Part A.

[42]  M. Kirschner,et al.  Geminin, an Inhibitor of DNA Replication, Is Degraded during Mitosis , 1998, Cell.

[43]  M. Abramowicz,et al.  Novel mutations in prenatal diagnosis of primary microcephaly , 2006, Prenatal diagnosis.

[44]  W. Ahmad,et al.  NOVEL PROTEIN-TRUNCATING MUTATIONS IN THE ASPM GENE IN FAMILIES WITH AUTOSOMAL RECESSIVE PRIMARY MICROCEPHALY , 2007, Journal of neurogenetics.

[45]  S. Pääbo,et al.  Mutations in mouse Aspm (abnormal spindle-like microcephaly associated) cause not only microcephaly but also major defects in the germline , 2010, Proceedings of the National Academy of Sciences.

[46]  H. Hennies,et al.  A truncating mutation of CEP135 causes primary microcephaly and disturbed centrosomal function. , 2012, American journal of human genetics.

[47]  H. Ropers,et al.  Establishment of a Mouse Model with Misregulated Chromosome Condensation due to Defective Mcph1 Function , 2010, PloS one.

[48]  P. Awadalla,et al.  Mutations in centrosomal protein CEP152 in primary microcephaly families linked to MCPH4. , 2010, American journal of human genetics.

[49]  Hussain Jafri,et al.  A centrosomal mechanism involving CDK5RAP2 and CENPJ controls brain size , 2005, Nature Genetics.

[50]  Soma Das,et al.  The first case of CDK5RAP2-related primary microcephaly in a non-consanguineous patient identified by next generation sequencing , 2014, Brain and Development.

[51]  Mitsuhiro Yanagida,et al.  Human Blinkin/AF15q14 is required for chromosome alignment and the mitotic checkpoint through direct interaction with Bub1 and BubR1. , 2007, Developmental cell.

[52]  H. Ropers,et al.  A clinical and molecular genetic study of 112 Iranian families with primary microcephaly , 2010, Journal of Medical Genetics.

[53]  Jaerak Chang,et al.  A novel function of CEP135 as a platform protein of C-NAP1 for its centriolar localization. , 2008, Experimental cell research.

[54]  T. Siddique,et al.  Genetic studies of autosomal recessive primary microcephaly in 33 Pakistani families: novel sequence variants in ASPM gene , 2006, Neurogenetics.

[55]  C. Woods,et al.  Autosomal recessive primary microcephaly: an analysis of locus heterogeneity and phenotypic variation , 2002, Journal of medical genetics.

[56]  Zhao-Qi Wang,et al.  DNA damage response in microcephaly development of MCPH1 mouse model. , 2013, DNA repair.

[57]  F. Alkuraya,et al.  Mutation in PHC1 implicates chromatin remodeling in primary microcephaly pathogenesis. , 2013, Human molecular genetics.

[58]  T. Tang,et al.  Identification of a novel microtubule-destabilizing motif in CPAP that binds to tubulin heterodimers and inhibits microtubule assembly. , 2004, Molecular biology of the cell.

[59]  S. Lenzner,et al.  SNP array-based homozygosity mapping reveals MCPH1 deletion in family with autosomal recessive mental retardation and mild microcephaly , 2006, Human Genetics.

[60]  Nelle Lambert,et al.  Kinetochore KMN network gene CASC5 mutated in primary microcephaly. , 2012, Human molecular genetics.

[61]  P. John,et al.  Previously described sequence variant in CDK5RAP2 gene in a Pakistani family with autosomal recessive primary microcephaly , 2007, BMC Medical Genetics.

[62]  D. Glover,et al.  Abnormal spindle protein, Asp, and the integrity of mitotic centrosomal microtubule organizing centers. , 1999, Science.

[63]  J. Rossiter,et al.  Recessive (true) microcephaly: a case report with neuropathological observations. , 1996, Journal of intellectual disability research : JIDR.

[64]  A. Desai,et al.  KNL1 and the CENP-H/I/K complex coordinately direct kinetochore assembly in vertebrates. , 2007, Molecular biology of the cell.

[65]  J. Raff,et al.  Maintaining the proper connection between the centrioles and the pericentriolar matrix requires Drosophila Centrosomin , 2007, The Journal of cell biology.

[66]  Chris P. Ponting,et al.  A novel domain suggests a ciliary function for ASPM, a brain size determining gene , 2006, Bioinform..

[67]  G. Pfeifer,et al.  CDK5RAP2 is required for spindle checkpoint function , 2009, Cell cycle.

[68]  H. Stark,et al.  The MIS12 complex is a protein interaction hub for outer kinetochore assembly , 2010, The Journal of cell biology.

[69]  P. Ingham,et al.  Microcephalin coordinates mitosis in the syncytial Drosophila embryo , 2007, Journal of Cell Science.

[70]  Cheol‐Hee Kim,et al.  The microcephaly gene aspm is involved in brain development in zebrafish. , 2011, Biochemical and biophysical research communications.

[71]  N. Tommerup,et al.  Genetic heterogeneity in Pakistani microcephaly families , 2013, Clinical genetics.

[72]  MANIFESTATIONS OF A RECESSIVE GENE FOR MICROCEPHALY IN A POPULATION ISOLATE. , 1964 .

[73]  Hussain Jafri,et al.  Identification of microcephalin, a protein implicated in determining the size of the human brain. , 2002, American journal of human genetics.

[74]  N. Tommerup,et al.  Compound heterozygous ASPM mutations in Pakistani MCPH families , 2009, American journal of medical genetics. Part A.

[75]  F. Alkuraya,et al.  Novel CENPJ mutation causes Seckel syndrome , 2010, Journal of Medical Genetics.

[76]  T. Komai,et al.  Genetic study of microcephaly based on Japanese material. , 1955, American journal of human genetics.

[77]  Stephan J Sanders,et al.  Whole exome sequencing identifies recessive WDR62 mutations in severe brain malformations , 2010, Nature.

[78]  I. Kirsch,et al.  Sil Phosphorylation in a Pin1 Binding Domain Affects the Duration of the Spindle Checkpoint , 2005, Molecular and Cellular Biology.

[79]  P. Robinson,et al.  Two Missense Mutations in the Primary Autosomal Recessive Microcephaly Gene MCPH1 Disrupt the Function of the Highly Conserved N-Terminal BRCT Domain of Microcephalin , 2012, Molecular Syndromology.

[80]  C. Norbury,et al.  The novel murine calmodulin-binding protein Sha1 disrupts mitotic spindle and replication checkpoint functions in fission yeast. , 1998, Journal of cell science.

[81]  C. Ponting,et al.  Evolution of primary microcephaly genes and the enlargement of primate brains. , 2005, Current opinion in genetics & development.

[82]  S. Raisamo,et al.  From , 2020, The Solace Is Not the Lullaby.

[83]  Xingzhi Xu,et al.  Microcephalin Is a DNA Damage Response Protein Involved in Regulation of CHK1 and BRCA1*♦ , 2004, Journal of Biological Chemistry.

[84]  Y. Terada,et al.  Interaction of Cep135 with a p50 dynactin subunit in mammalian centrosomes. , 2004, Cell motility and the cytoskeleton.

[85]  J. B. Rattner,et al.  CDK5RAP2 is a pericentriolar protein that functions in centrosomal attachment of the gamma-tubulin ring complex. , 2008, Molecular biology of the cell.

[86]  T. Tang,et al.  Depletion of CPAP by RNAi disrupts centrosome integrity and induces multipolar spindles. , 2006, Biochemical and biophysical research communications.

[87]  Martin Kircher,et al.  Transcriptomes of germinal zones of human and mouse fetal neocortex suggest a role of extracellular matrix in progenitor self-renewal , 2012, Proceedings of the National Academy of Sciences.

[88]  K. Shimotohno,et al.  Centrosomal P4.1-associated Protein Is a New Member of Transcriptional Coactivators for Nuclear Factor-κB* , 2005, Journal of Biological Chemistry.

[89]  J. VAN DEN BOSCH.  Microcephaly in the Netherlands: a clinical and genetical study. , 1959, Annals of human genetics.

[90]  Alexander F. Markham,et al.  ASPM is a major determinant of cerebral cortical size , 2002, Nature Genetics.

[91]  I Scala,et al.  Expanding the clinical and neuroradiologic phenotype of primary microcephaly due to ASPM mutations , 2009, Neurology.

[92]  C. Walsh,et al.  Protein-truncating mutations in ASPM cause variable reduction in brain size. , 2003, American journal of human genetics.

[93]  O. Ninnemann,et al.  CDK5RAP2 expression during murine and human brain development correlates with pathology in primary autosomal recessive microcephaly. , 2013, Cerebral cortex.

[94]  Shamik Dasgupta,et al.  The Drosophila homolog of MCPH1, a human microcephaly gene, is required for genomic stability in the early embryo , 2007, Journal of Cell Science.

[95]  I. Kirsch,et al.  The SIL gene is required for mouse embryonic axial development and left–right specification , 1999, Nature.

[96]  P. Lefebvre,et al.  Bld10p, a novel protein essential for basal body assembly in Chlamydomonas , 2004, The Journal of cell biology.

[97]  A. Farhadi,et al.  Investigation of primary microcephaly in Bushehr province of Iran: novel STIL and ASPM mutations , 2013, Clinical genetics.