Advertisement

Journal of Genetics

, Volume 96, Issue 2, pp 383–387 | Cite as

Molecular genetic analysis of consanguineous families with primary microcephaly identified pathogenic variants in the ASPM gene

  • MUZAMMIL AHMAD KHAN
  • CHRISTIAN WINDPASSINGER
  • MUHAMMAD ZEESHAN ALI
  • MUHAMMAD ZUBAIR
  • HADIA GUL
  • SAFDAR ABBAS
  • SAADULLAH KHAN
  • MUHAMMAD BADAR
  • RAMZI M. MOHAMMAD
  • ZAFAR NAWAZ
RESEARCH NOTE

Abstract

Autosomal recessive primary microcephaly is a rare genetic disorder that is characterized by reduced head circumference and a varying degree of intellectual disability. Genetic studies on consanguineous families with primary microcephaly have identified 15 (MCPH) causative genes that include MCPH1, WDR62, CDK5RAP2, CASC5, ASPM, CENPJ, STIL, CEP135, CEP152, ZNF335, PHC1, CDK6, CENPE, SASS6 MFSD2A ANKLE2 and CIT (Khan et al. 2014; Yamamoto et al. 2014; Alakbarzade et al. 2015; Morris-Rosendahl and Kaindl 2015; Basit et al. 2016). Physiologically, most of these MCPH proteins are involved in cell cycle and its regulation. In the present clinical genetic study, we have present two consanguineous Pakistani families segregating primary microcephaly and intellectual disability. These families were ascertained from the Saraiki ethnic part of Khyber-Pakhtunkhwa province in Pakistan. Whole exome sequencing in one family revealed a novel 1-bp deletion NM_018136.4: c.10013delA (p.Asp3338Valfs*2), while the other family showed a previously reported nonsense mutation NM_018136.4: c.9730C > T (rs199422195 (p.Arg3244*)) in ASPM gene. The novel frame-shift mutation (p.Asp3338Valfs*2) in ASPM presumably truncates the protein synthesis that results in loss of armadillo-type fold domain.

Keywords

primary microcephaly Pakistani families exome sequencing ASPM gene armadillo-type fold. 

Notes

Acknowledgements

We extend special thanks to all family members for their volunteer participation in this study. The current study is partially supported by startup research grant from Higher Education Commission of Pakistan (M-IPFP/HRD/HEC/2011/346) for molecular screening of neurological disorders. MAK appreciates the valuable contribution of his beloved nephew, Abdul Ahad Khan Gandapur in recruiting the family.

References

  1. Alakbarzade V., Hameed A., Quek D. Q. Y., Chioza B. A., Baple E. L., Cazenave-Gassiot A. et al. 2015 A partially inactivating mutation in the sodium-dependent lysophosphatidylcholine transporter MFSD2A causes a non-lethal microcephaly syndrome. Nat. Genet. 47, 814–817.CrossRefPubMedGoogle Scholar
  2. Barbelanne M. and Tsang W. Y. 2014 Molecular and cellular basis of autosomal recessive primary microcephaly. Biomed. Res. Int. 2014, 547986.CrossRefPubMedPubMedCentralGoogle Scholar
  3. Basit S., Al-Harbi K. M., Alhijje S. A. M., Albalaure A. M., Alharby E., Eldardear A. et al. 2016 CIT, a gene involved in neurogenic cytokinesis, is mutated in human primary microcephaly. Hum. Genet. 135, 1199–1207.CrossRefPubMedGoogle Scholar
  4. Baudier J., Deloulme J. C., Van Dorsselaer A., Black D. and Matthes H. W. 1991 Purification and characterization of a brain specific protein kinase C substrate, neurogranin (p17). Identification of a consensus amino acid sequence between neurogranin and neuromodulin (GAP43) that corresponds to the protein kinase C phosphorylation site and the calmodulin-binding domain. J. Biol. Chem. 266, 229–237.Google Scholar
  5. Bramham J., Hodgkinson J. L., Smith B. O., Uhrín D., Barlow P. N. and Winder S. J. 2002 Solution structure of the calponin CH domain and fitting to the 3D-helical reconstruction o F-actin: calponin. Structure 10, 249–258.CrossRefPubMedGoogle Scholar
  6. Coates J. C. 2003 Armadillo repeat proteins: beyond the animal kingdom. Trends. Cell. Biol. 13, 463–471.CrossRefPubMedGoogle Scholar
  7. do Carmo Avides M. and Glover D. M. 1999 Abnormal spindle protein, Asp, and the integrity of mitotic centrosomal microtubule organizing centers. Science 283, 1733–1735.CrossRefPubMedGoogle Scholar
  8. Gul A., Tariq M., Khan M. N., Hassan M. J., Ali G. and Ahmad W. 2007 Novel protein-truncating mutations in the ASPM gene in families with autosomal recessive primary microcephaly. J. Neurogenet. 21, 153–163.CrossRefPubMedGoogle Scholar
  9. Huber A. H., Nelson W. J. and Weis W. I. 1997 Three-dimensional structure of the armadillo repeat region of beta-catenin. Cell 90, 871–882.CrossRefPubMedGoogle Scholar
  10. Kamphans T. and Krawitz P. M. 2012 GeneTalk: an expert exchange platform for assessing rare sequence variants in personal genomes. Bioinformatics 28, 2515–2516.CrossRefPubMedPubMedCentralGoogle Scholar
  11. Khan M. A., Rupp V. M., Orpinell M., Hussain M. S., Altmuller J., Steinmetz M. O. et al. 2014 A missense mutation in the PISA domain of HsSAS-6 causes autosomal recessive primary microcephaly in a large consanguineous Pakistani family. Hum. Mol. Genet. 23, 5940–5949.CrossRefPubMedGoogle Scholar
  12. Leipe D. D., Koonin E. V. and Aravind L. 2004 STAND, a class of P-loop NTPases including animal and plant regulators of programmed cell death: multiple, complex domain architectures, unusual phyletic patterns, and evolution by horizontal gene transfer. J. Mol. Biol. 343, 1–28.CrossRefPubMedGoogle Scholar
  13. Mahmood S., Ahmad W. and Hassan M. J. 2011 Autosomal recessive primary microcephaly (MCPH): clinical manifestations, genetic heterogeneity and mutation continuum. Orphanet. J. Rare. Dis. 6, 39.CrossRefPubMedPubMedCentralGoogle Scholar
  14. Morris-Rosendahl D. J. and Kaindl A. M. 2015 What next-generation sequencing (NGS) technology has enabled us to learn about primary autosomal recessive microcephaly (MCPH). Mol. Cell. Probes 29, 271–281.CrossRefPubMedGoogle Scholar
  15. Nicholas A. K., Swanson E. A., Cox J. J., Karbani G., Malik S., Springell K. et al. 2009 The molecular landscape of ASPM mutations in primary microcephaly. J. Med. Genet. 46, 249–253.CrossRefPubMedGoogle Scholar
  16. Robinson P. N., Köhler S., Oellrich A., Wang K., Mungall C. J. et al. 2014 Sanger Mouse Genetics Project, Improved exome prioritization of disease genes through cross-species phenotype comparison. Genome Res. 24, 340–348.CrossRefPubMedPubMedCentralGoogle Scholar
  17. Smedley D., Köhler S., Czeschik J. C., Amberger J., Bocchini C., Hamosh A. et al. 2014 Walking the interactome for candidate prioritization in exome sequencing studies of Mendelian diseases. Bioinformatics 30, 3215–3222.CrossRefPubMedPubMedCentralGoogle Scholar
  18. Woods C. G., Bond J. and Enard W. 2005 Autosomal recessive primary microcephaly (MCPH): a review of clinical, molecular, and evolutionary findings. Am. J. Hum. Genet. 76, 717–728.CrossRefPubMedPubMedCentralGoogle Scholar
  19. Yamamoto S., Jaiswal M., Chang W. -L., Gambin T., Karaca E., Mirzaa G. et al. 2014 A Drosophila genetic resource of mutats to study mechanism underlying human genetic diseases. Cell 159, 200–214.CrossRefPubMedPubMedCentralGoogle Scholar
  20. Zemojtel T., Köhler S., Mackenroth L., Jäger M., Hecht J., Krawitz P. et al. 2014 Effective diagnosis of genetic disease by computational phenotype analysis of the disease-associated genome. Sci. Transl. Med. 6, 252ra123.CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© Indian Academy of Sciences 2017

Authors and Affiliations

  • MUZAMMIL AHMAD KHAN
    • 1
    • 2
  • CHRISTIAN WINDPASSINGER
    • 3
  • MUHAMMAD ZEESHAN ALI
    • 2
  • MUHAMMAD ZUBAIR
    • 2
    • 4
  • HADIA GUL
    • 5
  • SAFDAR ABBAS
    • 2
  • SAADULLAH KHAN
    • 1
    • 6
  • MUHAMMAD BADAR
    • 2
  • RAMZI M. MOHAMMAD
    • 1
  • ZAFAR NAWAZ
    • 1
    • 7
  1. 1.Translational Research Institute, Academic Health SystemHamad Medical CorporationDohaQatar
  2. 2.Gomal Centre of Biochemistry and BiotechnologyGomal University Dera Ismail KhanKhyber-PakhtoonkhwaPakistan
  3. 3.Institute of Human GeneticsMedical University of GrazGrazAustria
  4. 4.Department of Cell and Developmental Biology, School of Life SciencesUniversity of Science and Technology ChinaHefeiChina
  5. 5.Faculty of Sciences, Department of Biological SciencesGomal University Dera Ismail KhanKhyber-PakhtoonkhwaPakistan
  6. 6.Department of Biotechnology and Genetic EngineeringKohat University of Science and TechnologyKohatPakistan
  7. 7.Diagnostic Genomic Division, Department of Laboratory Medicine and PathologyHamad Medical CorporationDohaQatar

Personalised recommendations