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

被引:26
作者
Lo, Sarah M. [2 ]
Choi, Murim [3 ]
Liu, Jun
Jain, Dhanpat [4 ]
Boot, Rolf G. [5 ]
Kallemeijn, Wouter W. [5 ]
Aerts, Johannes M. F. G. [5 ]
Pashankar, Farzana [2 ]
Kupfer, Gary M. [2 ]
Mane, Shrikant [3 ]
Lifton, Richard P. [3 ]
Mistry, Pramod K. [1 ,6 ]
机构
[1] Yale Univ, Sch Med, Sect Digest Dis, Sect Pediat Gastroenterol & Hepatol,Dept Pediat, New Haven, CT 06520 USA
[2] Yale Univ, Sch Med, Dept Pediat, Sect Pediat Hematol Oncol, New Haven, CT 06520 USA
[3] Yale Univ, Sch Med, Dept Genet, Howard Hughes Med Inst, New Haven, CT 06520 USA
[4] Yale Univ, Sch Med, Dept Pathol, New Haven, CT 06520 USA
[5] Univ Amsterdam, Acad Med Ctr, Dept Biochem, NL-1105 AZ Amsterdam, Netherlands
[6] Yale Univ, Sch Med, Sect Digest Dis, Dept Internal Med, New Haven, CT 06520 USA
基金
美国国家卫生研究院;
关键词
MISMATCH REPAIR-DEFICIENCY; T-CELL LEUKEMIA; MICROSATELLITE INSTABILITY; LYSOSOMAL DISEASES; COLORECTAL-CANCER; EARLY-ONSET; MUTATIONS; MACROPHAGE; LYMPHOMA; MSH6;
D O I
10.1182/blood-2011-10-386862
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
Gaucher disease (GD), an inherited macrophage glycosphingolipidosis, manifests with an extraordinary variety of phenotypes that show imperfect correlation with mutations in the GBA gene. In addition to the classic manifestations, patients suffer from increased susceptibility to hematologic and nonhematologic malignancies. The mechanism(s) underlying malignancy in GD is not known, but is 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) mayunderlie the GD/cancer phenotype. In the present study, the genetic basis of GD/T-cell acute lymphoblastic lymphoma in 2 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 syndrome and increased cancer risk. Enzyme studies demonstrated that the D137N mutation in GBA is 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. (Blood. 2012; 119(20):4731-4740)
引用
收藏
页码:4731 / 4740
页数:10
相关论文
共 44 条
  • [1] Biomarkers in the diagnosis of lysosomal storage disorders: proteins, lipids, and inhibodies
    Aerts, Johannes M. F. G.
    Kallemeijn, Wouter W.
    Wegdam, Wouter
    Ferraz, Maria Joao
    van Breemen, Marielle J.
    Dekker, Nick
    Kramer, Gertjan
    Poorthuis, Ben J.
    Groener, Johanna E. M.
    Cox-Brinkman, Josanne
    Rombach, Saskia M.
    Hollak, Carla E. M.
    Linthorst, Gabor E.
    Witte, Martin D.
    Gold, Henrik
    van der Marel, Gijs A.
    Overkleeft, Herman S.
    Boot, Rolf G.
    [J]. JOURNAL OF INHERITED METABOLIC DISEASE, 2011, 34 (03) : 605 - 619
  • [2] Molecular pathogenesis of T-cell leukaemia and lymphoma
    Aifantis, Iannis
    Raetz, Elizabeth
    Buonamici, Silvia
    [J]. NATURE REVIEWS IMMUNOLOGY, 2008, 8 (05) : 380 - 390
  • [3] Gaucher disease: Variability in phenotype among siblings
    Amato, D
    Stachiw, T
    Clarke, JTR
    Rivard, GE
    [J]. JOURNAL OF INHERITED METABOLIC DISEASE, 2004, 27 (05) : 659 - 669
  • [4] Evidence for a link between sphingolipid metabolism and expression of CD1d and MHC-class II: monocytes from Gaucher disease patients as a model
    Balreira, A
    Lacerda, L
    Miranda, CS
    Arosa, FA
    [J]. BRITISH JOURNAL OF HAEMATOLOGY, 2005, 129 (05) : 667 - 676
  • [5] Uncoupling between CD1d upregulation induced by retinoic acid and conduritol-B-epoxide and iNKT cell responsiveness
    Balreira, Andrea
    Cavallari, Marco
    Miranda, Maria Clara Sa
    Arosa, Fernando A.
    [J]. IMMUNOBIOLOGY, 2010, 215 (06) : 505 - 513
  • [6] Syndrome of early onset colon cancers, hematologic malignancies & features of neurofibromatosis in HNPCC families with homozygous mismatch repair gene mutations
    Bandipalliam, P
    [J]. FAMILIAL CANCER, 2005, 4 (04) : 323 - 333
  • [7] Dendritic cell and macrophage infiltration in microsatellite-unstable and microsatellite-stable colorectal cancer
    Bauer, Kathrin
    Michel, Sara
    Reuschenbach, Miriam
    Nelius, Nina
    Doeberitz, Magnus von Knebel
    Kloor, Matthias
    [J]. FAMILIAL CANCER, 2011, 10 (03) : 557 - 565
  • [8] Discrepancies between genotype and phenotype in hematology: an important frontier
    Beutler, E
    [J]. BLOOD, 2001, 98 (09) : 2597 - 2602
  • [9] The biochemical basis of microsatellite instability and abnormal immunohistochemistry and clinical behavior in Lynch Syndrome: from bench to bedside
    Boland, C. Richard
    Koi, Minoru
    Chang, Dong K.
    Carethers, John M.
    [J]. FAMILIAL CANCER, 2008, 7 (01) : 41 - 52
  • [10] Gaucher cells demonstrate a distinct macrophage phenotype and resemble alternatively activated macrophages
    Boven, LA
    van Meurs, M
    Boot, RG
    Mehta, A
    Boon, L
    Aerts, JM
    Laman, JD
    [J]. AMERICAN JOURNAL OF CLINICAL PATHOLOGY, 2004, 122 (03) : 359 - 369