Protein-truncating mutations in ASPM cause variable reduction in brain size.
Mutations in the ASPM gene at the MCPH5 locus are expected to be the most common cause of human autosomal recessive primary microcephaly (MCPH), a condition in which there is a failure of normal fetal brain development, resulting in congenital microcephaly and mental retardation. We have performed the first comprehensive mutation screen of the 10.4-kb ASPM gene, identifying all 19 mutations in a cohort of 23 consanguineous families. Mutations occurred throughout the ASPM gene and were all predicted to be protein truncating. Phenotypic variation in the 51 affected individuals occurred in the degree of microcephaly (5-11 SDs below normal) and of mental retardation (mild to severe) but appeared independent of mutation position.
Bond
Jacquelyn
J
Molecular Medicine Unit, University of Leeds, St. James's University Hospital, Leeds, United Kingdom. j.bond@leeds.ac.uk
Scott
Sheila
S
Hampshire
Daniel J
DJ
Springell
Kelly
K
Corry
Peter
P
Abramowicz
Marc J
MJ
Mochida
Ganesh H
GH
Hennekam
Raoul C M
RC
Maher
Eamonn R
ER
Fryns
Jean-Pierre
JP
Alswaid
Abdulrahman
A
Jafri
Hussain
H
Rashid
Yasmin
Y
Mubaidin
Ammar
A
Walsh
Christopher A
CA
Roberts
Emma
E
Woods
C Geoffrey
CG
D000595:Amino Acid Sequence; D001483:Base Sequence; D001921:Brain / Q000002:abnormalities* / Q000378:metabolism* / Q000473:pathology; D002878:Chromosomes, Human, Pair 1 / Q000235:genetics; D018389:Codon, Nonsense / Q000235:genetics; D003241:Consanguinity; D004252:DNA Mutational Analysis; D005091:Exons / Q000235:genetics; D016368:Frameshift Mutation / Q000235:genetics; D005808:Genes, Recessive / Q000235:genetics; D006239:Haplotypes / Q000235:genetics; D006801:Humans; D008607:Intellectual Disability / Q000150:complications / Q000235:genetics / Q000503:physiopathology; D007438:Introns / Q000235:genetics; D008297:Male; D008831:Microcephaly / Q000150:complications / Q000235:genetics* / Q000473:pathology; D018895:Microsatellite Repeats / Q000235:genetics; D009154:Mutation / Q000235:genetics*; D009419:Nerve Tissue Proteins / Q000235:genetics*; D010154:Pakistan; D010641:Phenotype; D011110:Polymorphism, Genetic / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism
C467202:ASPM protein, human; D018389:Codon, Nonsense; D009419:Nerve Tissue Proteins; D012333:RNA, Messenger