한빛사논문
Abstract
Sarah M. Lo*,1 Murim Choi*,2 Jun Liu,3 Dhanpat Jain,4 Rolf G. Boot,5 Wouter W. Kallemeijn,5 Johannes
M. F. G. Aerts,5 Farzana Pashankar,1 Gary M. Kupfer,1 Shrikant Mane,2 and Richard P. Lifton,2 and
Pramod K. Mistry.3,6,†
* These authors contributed equally
1Section of Pediatric Hematology-Oncology, Department of Pediatrics, Yale School of Medicine, New Haven, Connecticut, USA; 2Howard Hughes Medical Institute, Department of Genetics, Yale School of
Medicine, New Haven, Connecticut, USA; 3Section of Pediatric Gastroenterology-Hepatology, Department of Pediatrics, Yale School of Medicine, New Haven, Connecticut, USA; 4Department of Pathology, Yale School of Medicine, New Haven, Connecticut, USA; 5Department of Biochemistry, Academic Medical Centre, Amsterdam, the Netherlands; 6Section of Digestive Diseases, Department of Internal Medicine, Yale School of Medicine, New Haven, Connecticut, USA.
† Correspondence to Pramod K. Mistry, Professor of Pediatrics and Medicine, Section of Pediatric Gastroenterology and Hepatology, Section of Digestive Diseases, Yale University School of Medicine, 333 Cedar Street, P.O. Box 208064, New Haven, CT 06520-8064.
Abstract
Gaucher disease (GD), an inherited macrophage glycosphinglipidosis, manifests with extraordinary variation of phenotypes, which show imperfect correlation with mutations in the GBA gene. In addition to the classic manifestations, patients suffer from increased susceptibility to hematologic and non-hematologic malignancies. The mechanism(s) underlying malignancy in GD is not known, but postulated to be secondary to macrophage dysfunction and immune dysregulation arising from lysosomal accumulation of glucocerebroside. However, there is weak correlation between GD/cancer phenotype and the systemic burden of glucocerebroside-laden macrophages. Therefore, we hypothesized that genetic modifier(s) may underlie the GD/cancer phenotype. The genetic basis of GD/T-cell acute lymphoblastic lymphoma (T-LBL) in two affected siblings was deciphered through genomic analysis. GBA gene sequencing revealed homozygosity for a novel mutation, D137N. Whole exome capture and massively parallel sequencing combined with homozygosity mapping identified a homozygous novel mutation in the MSH6 gene that leads to constitutional mismatch repair deficiency (CMMRD) syndrome and increased cancer risk. Enzyme studies demonstrated D137N mutation in GBA to be a pathogenic mutation, and immunohistochemistry confirmed the absence of the MSH6 protein. Therefore, precise phenotype annotation followed by individual genome analysis has the potential to identify genetic modifiers of GD, facilitate personalized management, and provide novel insights into disease pathophysiology.
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