Advertisement

Identification of a novel GLB1 mutation in a consanguineous Pakistani family affected by rare infantile GM1 gangliosidosis

  • Bibi Zubaida
  • Muhammad Almas Hashmi
  • Huma Arshad Cheema
  • Muhammad Naeem
Research Note

Abstract

Monosialotetrahexosylganglioside (GM1) is a rare lysosomal storage disorder caused by the deficiency of beta-galactosidase (\(\upbeta \)-Gal) encoded by galactose beta 1 (GLB1). It is clinically characterized by developmental delay attributed to multifold accumulation of GM1 gangliosides in nerve cells. In this study, we present a case of infantile GM1 gangliosidosis in a consanguineous Pakistani family. The child was presented with developmental delay, hepatosplenomegaly and recurrent chest infections at 7.5 months of age. Radiological and biochemical investigations including magnetic resonance imaging (MRI), bone marrow biopsy and urine oligosaccharide analyses suggested lysosomal storage disorder. Significantly low levels of \(\upbeta \)-Gal enzyme confirmed the diagnosis of GM1 gangliosidosis. DNA sequencing of GLB1 identified a homozygous 2-bp deletion c.881-882delAT (p.Tyr294Terfs) in exon 8. In silico analysis supported the deleterious effect of the variant. This study extends GLB1 mutation spectrum and should benefit genetic counselling and prenatal diagnosis of the affected family.

Keywords

GM1 gangliosidosis beta-galactosidase novel mutation GLB1 gene 

Notes

Acknowledgements

We thank the family members for participating in this study. The Higher Education Commission of Pakistan is acknowledged for supporting B. Z. under an Indigenous Ph.D. Fellowship scheme (PIN: 213-52789-2BM2). This research did not receive any specific grant from funding agencies in the public, commercial or not-for-profit sectors.

References

  1. Caciotti A., Donati M. A., Boneh A., d’Azzo A., Federico A., Parini R. et al. 2005 Role of beta-galactosidase and elastin binding protein in lysosomal and nonlysosomal complexes of patients with GM1-gangliosidosis. Hum. Mutat.  25, 285–292.CrossRefGoogle Scholar
  2. Caciotti A., Garman S. C., Rivera-Colon Y., Procopio E., Catarzi S., Ferri L. et al. 2011 GM1 gangliosidosis and Morquio B disease: an update on genetic alterations and clinical findings. Biochim. Biophys. Acta. 1812, 782–790.CrossRefGoogle Scholar
  3. Callahan J. W. 1999 Molecular basis of GM1 gangliosidosis and Morquio disease, type B. Structure-function studies of lysosomal beta-galactosidase and the non-lysosomal beta-galactosidase-like protein. Biochim. Biophys. Acta. 1455, 85–103.CrossRefGoogle Scholar
  4. Gururaj A., Sztriha L., Hertecant J., Johansen J. G., Georgiou T., Campos Y. et al. 2005 Magnetic resonance imaging findings and novel mutations in GM1 gangliosidosis. J. Child. Neurol. 20, 57–60.CrossRefGoogle Scholar
  5. Hall T. A. 1999 BioEdit: a user-friendly biological sequence alignment editor and analysis program for Windows 95/98/NT. Nucleic Acids Symp. Ser. 41, 95–98.Google Scholar
  6. Hinek A., Zhang S., Smith A. C. and Callahan J. W. 2000 Impaired elastic-fiber assembly by fibroblasts from patients with either Morquio B disease or infantile GM1-gangliosidosis is linked to deficiency in the 67-kD spliced variant of beta-galactosidase. Am. J. Hum. Genet67, 23–36.CrossRefGoogle Scholar
  7. Hofer D., Paul K., Fantur K., Beck M., Roubergue A., Vellodi A. et al. 2010 Phenotype determining alleles in GM1 gangliosidosis patients bearing novel GLB1 mutations. Clin. Genet78, 236–246.CrossRefGoogle Scholar
  8. Nishimoto J., Nanba E., Inui K., Okada S. and Suzuki K. 1991 GM1-gangliosidosis (genetic beta-galactosidase deficiency): identification of four mutations in different clinical phenotypes among Japanese patients. Am. J. Hum. Genet49, 566–574.PubMedPubMedCentralGoogle Scholar
  9. Ohto U., Usui K., Ochi T., Yuki K., Satow Y. and Shimizu T. 2012 Crystal structure of human beta-galactosidase: structural basis of GM1 gangliosidosis and morquio B diseases. J. Biol. Chem287, 1801–1812.CrossRefGoogle Scholar
  10. Oshima A., Tsuji A., Nagao Y., Sakuraba H. and Suzuki Y. 1988 Cloning, sequencing, and expression of cDNA for human beta-galactosidase. Biochem. Biophys. Res. Commun157, 238–244.CrossRefGoogle Scholar
  11. Richards S., Aziz N., Bale S., Bick D., Das S., Gastier-Foster J. et al. 2015 Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet. Med17, 405–424.CrossRefGoogle Scholar
  12. Sandhoff K. and Harzer K. 2013 Gangliosides and gangliosidoses: principles of molecular and metabolic pathogenesis. J. Neurosci33, 10195–10208.CrossRefGoogle Scholar
  13. Santamaria R., Chabas A., Coll M. J., Miranda C. S., Vilageliu L. and Grinberg D. 2006 Twenty-one novel mutations in the GLB1 gene identified in a large group of GM1-gangliosidosis and Morquio B patients: possible common origin for the prevalent p.R59H mutation among gypsies. Hum. Mutat27, 1060.CrossRefGoogle Scholar
  14. Santamaria R., Chabas A., Callahan J. W., Grinberg D. and Vilageliu L. 2007 Expression and characterization of 14 GLB1 mutant alleles found in GM1-gangliosidosis and Morquio B patients. J. Lipid. Res48, 2275–2282.CrossRefGoogle Scholar
  15. Takano T. and Yamanouchi Y. 1993 Assignment of human beta-galactosidase-A gene to 3p21.33 by fluorescence in situ hybridization. Hum. Genet92, 403–404.CrossRefGoogle Scholar
  16. Yoshida K., Oshima A., Shimmoto M., Fukuhara Y., Sakuraba H., Yanagisawa N. et al. 1991 Human beta-galactosidase gene mutations in GM1-gangliosidosis: a common mutation among Japanese adult/chronic cases. Am. J. Hum. Genet.  49, 435–442.PubMedPubMedCentralGoogle Scholar

Copyright information

© Indian Academy of Sciences 2018

Authors and Affiliations

  1. 1.Medical Genetics Research Laboratory, Department of BiotechnologyQuaid-i-Azam UniversityIslamabadPakistan
  2. 2.Department of Pediatric GastroenterologyThe Children’s Hospital and the Institute of Child HealthLahorePakistan

Personalised recommendations