Abstract
Human autosomal recessive primary microcephaly (MCPH) is a rare genetic disorder in which affected individuals are born with reduced brain size. MCPH is genetically heterogeneous, with six loci and four genes reported to date. Mutations in the ASPM gene at the MCPH5 locus appear to be the most common cause of MCPH. For this study, 33 Pakistani families with primary microcephaly were enrolled. Genotyping using microsatellite markers linked to the six known MCPH loci showed the linkage of 18 families to the MCPH5 locus, two to the MCPH2 locus, two to the MCPH4 locus, and one to the MCPH6 locus. The remaining ten families were not linked to any of the known loci. Families linked to the MCPH5 locus were further subjected to screening of the ASPM gene with direct DNA sequencing. Two previously reported variants, 3978G>A (W1326X) and 9557C>G (S3186X), were observed in five Pakistani families. Four novel nonsynonymous sequence variants, 9118insCATT, 9238A>T (L3080X), 9539A>C (Q3180P), and 1260delTCAAGTC, were found to segregate within four families, but were not observed in 200 Pakistani control chromosomes. One of the variants, 9539A>C (Q3180P), occurred in the IQ 79 domain, but its functional significance awaits definition.
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Acknowledgements
We wish to thank the members of the families for their cooperation. The work presented was funded by the Islamic Educational, Scientific and Cultural Organisation, Rabat, Morocco; the Higher Education Commission (HEC), Islamabad, Pakistan; the Herbert and Florence C. Wenske Foundation; the Vena E. Schaff Amyotrophic Lateral Sclerosis Research Fund; the Abbott Labs Duane and Susan Burnham Professorship; and the Ralph and Marian Falk Medical Research Trust. Asma Gul, Muhammad Jawad Hassan, and Muhammad Salman Chishti were supported by indigenous Ph.D. fellowships from HEC, Islamabad, Pakistan.
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Gul, A., Hassan, M.J., Mahmood, S. et al. Genetic studies of autosomal recessive primary microcephaly in 33 Pakistani families: novel sequence variants in ASPM gene. Neurogenetics 7, 105–110 (2006). https://doi.org/10.1007/s10048-006-0042-4
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DOI: https://doi.org/10.1007/s10048-006-0042-4