title: Mutations in STIL, encoding a pericentriolar and centrosomal protein, cause primary microcephaly.
abstract: Primary microcephaly (MCPH) is an autosomal-recessive congenital disorder characterized by smaller-than-normal brain size and mental retardation. MCPH is genetically heterogeneous with six known loci: MCPH1-MCPH6. We report mapping of a novel locus, MCPH7, to chromosome 1p32.3-p33 between markers D1S2797 and D1S417, corresponding to a physical distance of 8.39 Mb. Heterogeneity analysis of 24 families previously excluded from linkage to the six known MCPH loci suggested linkage of five families (20.83%) to the MCPH7 locus. In addition, four families were excluded from linkage to the MCPH7 locus as well as all of the six previously known loci, whereas the remaining 15 families could not be conclusively excluded or included. The combined maximum two-point LOD score for the linked families was 5.96 at marker D1S386 at theta = 0.0. The combined multipoint LOD score was 6.97 between markers D1S2797 and D1S417. Previously, mutations in four genes, MCPH1, CDK5RAP2, ASPM, and CENPJ, that code for centrosomal proteins have been shown to cause this disorder. Three different homozygous mutations in STIL, which codes for a pericentriolar and centrosomal protein, were identified in patients from three of the five families linked to the MCPH7 locus; all are predicted to truncate the STIL protein. Further, another recently ascertained family was homozygous for the same mutation as one of the original families. There was no evidence for a common haplotype. These results suggest that the centrosome and its associated structures are important in the control of neurogenesis in the developing human brain.
authors.affiliation: Department of Molecular Reproduction, Development and Genetics, Indian Institute of Science, Bangalore 560012, India. karun@mrdg.iisc.ernet.in
authors.forename: Arun
authors.initials: A
authors.lastname: Kumar
authors.forename: Satish C
authors.initials: SC
authors.lastname: Girimaji
authors.forename: Mahesh R
authors.initials: MR
authors.lastname: Duvvari
authors.forename: Susan H
authors.initials: SH
authors.lastname: Blanton
mesh_terms: D001921:Brain / Q000002:abnormalities / Q000033:anatomy & histology; D018797:Cell Cycle Proteins; D018385:Centrosome / Q000502:physiology; D003598:Cytoskeletal Proteins; D004247:DNA / Q000235:genetics; D005190:Family; D005260:Female; D005819:Genetic Markers; D006801:Humans; D008607:Intellectual Disability / Q000235:genetics; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics*; D008297:Male; D008831:Microcephaly / Q000235:genetics*; D008869:Microtubule-Associated Proteins / Q000235:genetics; D009154:Mutation; D009419:Nerve Tissue Proteins / Q000235:genetics
chemical_list: C467202:ASPM protein, human; C414735:CENPJ protein, human; D018797:Cell Cycle Proteins; D003598:Cytoskeletal Proteins; D005819:Genetic Markers; D047908:Intracellular Signaling Peptides and Proteins; C460645:MCPH1 protein, human; D008869:Microtubule-Associated Proteins; D009419:Nerve Tissue Proteins; C071236:STIL protein, human; D004247:DNA