Phenotype diversity in type 1 Gaucher disease: discovering the genetic basis of Gaucher disease/hematologic malignancy phenotype by individual genome analysis

Lo, Sarah M.; Choi, Murim; Li, Jun; Jain, Dhanpat; Boot, Rolf G.; Kallemeijn, Wouter W.; Aerts, Johannes M. F. G.; Pashankar, Farzana; Kupfer, Gary M.; Mane, Shrikant; Lifton, Richard P.; Mistry, Pramod K.

doi:10.1182/blood-2011-10-386862

Cited by 38 publications

(24 citation statements)

References 39 publications

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“…performed whole‐exome capture and massively parallel sequencing on DNA samples of two siblings with type 1 GD and T‐cell acute lymphoblastic lymphoma. They found a novel homozygous mutation in MSH6 (mutS homolog 6), which could disrupt the patients’ mismatch repair system and contribute to their cancer (Lo et al., ). As Mistry et al.…”

Section: Modifiers May Mediate Other Gaucher‐associated Disordersmentioning

confidence: 99%

Exploring genetic modifiers of Gaucher disease: The next horizon

et al. 2018

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Gaucher disease is an autosomal recessive lysosomal storage disorder resulting from mutations in the gene GBA1 that lead to a deficiency in the enzyme glucocerebrosidase. Accumulation of the enzyme's substrates, glucosylceramide and glucosylsphingosine, results in symptoms ranging from skeletal and visceral involvement to neurological manifestations. Nonetheless, there is significant variability in clinical presentations amongst patients, with limited correlation between genotype and phenotype. Contributing to this clinical variation are genetic modifiers that influence the phenotypic outcome of the disorder. In this review, we explore the role of genetic modifiers in Mendelian disorders and describe methods to facilitate their discovery. In addition, we provide examples of candidate modifiers of Gaucher disease, explore their relevance in the development of potential therapeutics, and discuss the impact of GBA1 and modifying mutations on other more common diseases like Parkinson disease. Identifying these important modulators of Gaucher phenotype may ultimately unravel the complex relationship between genotype and phenotype and lead to improved counseling and treatments.

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Section: Modifiers May Mediate Other Gaucher‐associated Disordersmentioning

confidence: 99%

Exploring genetic modifiers of Gaucher disease: The next horizon

et al. 2018

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“…This latter type of phenotypic variation is likely to be determined by the impact of modifier gene(s) with a large effect. For example, biallelic mutation in the MSH6 gene 69 and JAK2 mutations 26 have been described as underlying T-cell lymphoblastic lymphoma and myeloproliferative malignancy, respectively, in GD1.…”

Section: Pathogenesis Of Cancers In Gdmentioning

confidence: 99%

Gaucher Disease and Malignancy: A Model for Cancer Pathogenesis in an Inborn Error of Metabolism

et al. 2013

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Clinical observations spanning almost half a century have demonstrated a consistent association of type 1 Gaucher disease (GD1) and cancers. However, the cellular and molecular bases of the association are not understood. Gaucher disease (GD) is a lysosomal storage disorder due to an inherited deficiency of acid β-glucosidase that underlies the accumulation of glucosylceramide in lysosomes of mononuclear phagocytes and immune dysregulation. The overall cancer risk is markedly increased in GD, and the determinants of malignancy in a subset of patients with GD1 are not known. The association of GD and cancer is most striking for hematological malignancies, with the risk for multiple myeloma estimated at almost 37-fold compared to the general population; some studies have also suggested increased cancer risk for non-hematological malignancies. There is no association of overall severity of GD to risk of cancer, although there is an increased prevalence of splenectomy among patients exhibiting the GD/cancer phenotype. Moreover, there appears to be an increased incidence of multiple consecutive cancers in individual patients. Several factors could contribute to cancer development in GD, including polarization of macrophages to the alternatively activated phenotype, chronic inflammation, chronic B-cell stimulation, splenectomy, hyperferritinemia, lysosomal dysfunction, and endoplasmic reticulum stress. Recent studies have highlighted T-cell dysfunction and modifier genes contributing to an increased cancer risk in GD. Macrophage-targeted enzyme replacement therapy (ERT) reverses systemic features of GD1; while cancer risk appears to be reduced in the era of ERT, it is not known whether this is a direct effect of therapy. Delineation of the mechanisms underlying the increased cancer risk in GD will provide additional novel insights into the role of lipids and macrophages in cancer pathogenesis and, moreover, have the potential to reveal novel therapeutic targets.

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“…Further studies are required to see if there is evidence of association of GBA1 gene with CAMTA1, WWTR1, and MYC oncogenes. Similar association of GD with T cell lymphoblastic lymphoma has been described due to presence of MHS6 gene mutation [22].…”

Section: Discussionmentioning

confidence: 63%

Case series and literature review of skeletal tumors and their incidence in the Gaucher disease population

et al. 2016

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An Ashkenazi Jewish male first presented at age 40 with persistent bone pain and a tender mass on his right leg. This patient was the subject of a prior case report in 1995 [1]. He had onset of persistent bone pain and splenomegaly at age 5 years and at age 10 suffered from avascular osteonecrosis of the right femur. At age 15 years, he suffered from recurrent avascular necrosis of right femur and right humerus. Diagnosis of Gaucher Disease (GD) Type 1 was made on bone marrow biopsy, later confirmed by low leucocyte acid b-glucosidase activity and the finding of homozygosity for N370S mutation in GBA gene. He underwent osteotomy of his right hip at age 18. At age 25 years, the patient suffered from infectious mononucleosis resulting in massive splenomegaly and splenic rupture that necessitated emergency splenectomy. Subsequently, he underwent right hip replacement. At his presentation with right leg mass, the mass and bone pain had been present for the previous 6 months and had worsened until the patient could no longer continue his daily activities. At this time in 1992, enzyme replacement therapy had not yet become the standard of care for GD.Gaucher disease, an autosomal recessive disorder, is a prototype inborn error of metabolism due to biallelic mutations in GBA1 that results in deficiency of lysosomal acid b-glucocerebrosidase, a key enzyme in the degradation pathway of membrane glycosphingolipids [2]. GD displays a heterogeneous clinical presentation affecting multiple organs with major skeletal involvement based on the accumulation of glucocerebroside-laden macrophages, eponymously known as Gaucher cells [3]. The accumulation of primary substrate leads to generation of bioactive lipids that cause immune activation and chronic metabolic inflammation [4,5]. Bone disease was more common and more severe in asplenic patients with GD [2]. In fact, asplenia is a major independent risk factor for avascular osteonecrosis [6].Plain radiographs of tibia showed typical bony lesions of Gaucher disease including osteopenia, extensive bone marrow infarcts, and lytic lesions. In addition, there was a focal mass concerning for a malignant tumor. The tibia was resected and replaced with intercalary allograft, soleus muscle flap, and split thickness skin graft. Subsequently, infectious complications necessitated an above knee amputation.On gross examination, the tumor measured 4 3 4 3 3 cm and was focally friable and hemorrhagic. The tumor was dispersed in sheets and cords within a hyalinized basophilic background. Intensely eosinophilic nucleoli, abundant cytoplasm, and cytoplasmic vacuoles with red blood cells were present. The extraosseous segment showed increasing atypia with primitive anastomosing split like vascular spaces. The bone marrow was extensively necrotic and demonstrated infiltration by Gaucher cells. By immunohistochemistry, the cells stained positive for keratin, factor VIII antigen, Ulex europaeus agglutinin, and vimentin [1]. The cells demonstrated a high nuclear cytoplasmic ratio with striking euchrom...

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Phenotype diversity in type 1 Gaucher disease: discovering the genetic basis of Gaucher disease/hematologic malignancy phenotype by individual genome analysis

Cited by 38 publications

References 39 publications

Exploring genetic modifiers of Gaucher disease: The next horizon

Exploring genetic modifiers of Gaucher disease: The next horizon

Gaucher Disease and Malignancy: A Model for Cancer Pathogenesis in an Inborn Error of Metabolism

Case series and literature review of skeletal tumors and their incidence in the Gaucher disease population

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