Abstract
We report the modulating action of the L436F new polymorphism identified in the GLB1 gene of a patient affected by GM1 gangliosidosis with onset at 17 months and rapidly progressive psychomotor deterioration. Sequencing analysis and familial restriction studies revealed that the maternal allele of this patient carried the L436F polymorphism in cis with the known R201C mutation. The new mutation R68W was identified in his paternal allele. Since the GLB1 activity of the patient's leukocytes was very low and compatible with both the type-I and the type-II form of the disease, the potential impact of each mutation was investigated by expression studies in COS1 cells, and Western blots. Expression study of the R68W mutated allele resulted in no GLB1 activity. Transfection with a vector carrying the R201C mutation gave rise to a residual GLB1 activity, which, interestingly, was severely reduced in transfection with the L436F/R201C allele. These expression studies, together with co-transfection experiments, suggest that the R201C/L436F GLB1 "complex allele" leads to this patient's clinical and biochemical findings. The type-II phenotype of the disease is subdivided into late infantile and juvenile forms. The clinical and molecular characterization of this patient as late-infantile GM1 gangliosidosis is in keeping with a clear-cut division between the two sub forms of the type-II phenotype. The modulating role of the L436F polymorphism should be stressed as a cause of this patient's condition. This model suggests that the combination of missense mutations or polymorphisms should be evaluated when diagnosing inherited genetic disorders.
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Acknowledgements
This work was partially supported by grants: Fondi Ateneo (MURST ex 60%) Azienda Ospedaliera Meyer, Association AMMEC and MPS Italy, NIH grants DK/NS52025 and GM60950 and Y. Campos by the Assisi Foundation of Memphis.
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Caciotti, A., Bardelli, T., Cunningham, J. et al. Modulating action of the new polymorphism L436F detected in the GLB1 gene of a type-II GM1 gangliosidosis patient. Hum Genet 113, 44–50 (2003). https://doi.org/10.1007/s00439-003-0930-8
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DOI: https://doi.org/10.1007/s00439-003-0930-8