title: Combined immunodeficiency due to MALT1 mutations, treated by hematopoietic cell transplantation.
abstract: OBJECTIVE
  A male infant developed generalized rash, intestinal inflammation and severe infections including persistent cytomegalovirus. Family history was negative, T cell receptor excision circles were normal, and engraftment of maternal cells was absent. No defects were found in multiple genes associated with severe combined immunodeficiency. A 9/10 HLA matched unrelated hematopoietic cell transplant (HCT) led to mixed chimerism with clinical resolution. We sought an underlying cause for this patient's immune deficiency and dysregulation.
  
  
  METHODS
  Clinical and laboratory features were reviewed. Whole exome sequencing and analysis of genomic DNA from the patient, parents and 2 unaffected siblings was performed, revealing 2 MALT1 variants. With a host-specific HLA-C antibody, we assessed MALT1 expression and function in the patient's post-HCT autologous and donor lymphocytes. Wild type MALT1 cDNA was added to transformed autologous patient B cells to assess functional correction.
  
  
  RESULTS
  The patient had compound heterozygous DNA variants affecting exon 10 of MALT1 (isoform a, NM_006785.3), a maternally inherited splice acceptor c.1019-2A > G, and a de novo deletion of c.1059C leading to a frameshift and premature termination. Autologous lymphocytes failed to express MALT1 and lacked NF-κB signaling dependent upon the CARMA1, BCL-10 and MALT1 signalosome. Transduction with wild type MALT1 cDNA corrected the observed defects.
  
  
  CONCLUSIONS
  Our nonconsanguineous patient with early onset profound combined immunodeficiency and immune dysregulation due to compound heterozygous MALT1 mutations extends the clinical and immunologic phenotype reported in 2 prior families. Clinical cure was achieved with mixed chimerism after nonmyeloablative conditioning and HCT.
authors: Department of Pediatrics, University of California San Francisco School of Medicine, and UCSF Benioff Children's Hospital, Box 0519, 513 Parnassus Avenue, HSE-301A, San Francisco, CA, 94143-0519, USA.
authors: Divya
authors: D
authors: Punwani
authors: Haopeng
authors: H
authors: Wang
authors: Alice Y
authors: AY
authors: Chan
authors: Morton J
authors: MJ
authors: Cowan
authors: Jacob
authors: J
authors: Mallott
authors: Uma
authors: U
authors: Sunderam
authors: Marianne
authors: M
authors: Mollenauer
authors: Rajgopal
authors: R
authors: Srinivasan
authors: Steven E
authors: SE
authors: Brenner
authors: Arend
authors: A
authors: Mulder
authors: Frans H J
authors: FH
authors: Claas
authors: Arthur
authors: A
authors: Weiss
authors: Jennifer M
authors: JM
authors: Puck
mesh_terms: D000328:Adult; D000595:Amino Acid Sequence; D001402:B-Lymphocytes / Q000378:metabolism / Q000821:virology; D001483:Base Sequence; D020169:Caspases / Q000235:genetics* / Q000378:metabolism; D002461:Cell Line, Transformed; D002648:Child; D002675:Child, Preschool; D004252:DNA Mutational Analysis; D005260:Female; D015870:Gene Expression; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D016130:Immunophenotyping; D007223:Infant; D007231:Infant, Newborn; D007963:Leukocytes, Mononuclear / Q000276:immunology / Q000378:metabolism; D008297:Male; D000074884:Mucosa-Associated Lymphoid Tissue Lymphoma Translocation 1 Protein; D009154:Mutation; D016328:NF-kappa B / Q000378:metabolism; D009363:Neoplasm Proteins / Q000235:genetics* / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D016511:Severe Combined Immunodeficiency / Q000175:diagnosis / Q000235:genetics* / Q000378:metabolism / Q000628:therapy*; D015398:Signal Transduction; D012867:Skin / Q000473:pathology; D018183:Transplantation Chimera; D014184:Transplantation, Homologous
chemical_list: D016328:NF-kappa B; D009363:Neoplasm Proteins; D012333:RNA, Messenger; D020169:Caspases; C400109:MALT1 protein, human; D000074884:Mucosa-Associated Lymphoid Tissue Lymphoma Translocation 1 Protein
references: Curr Opin Pediatr. 2011 Dec;23(6):667-73
references: 22001765
references: J Allergy Clin Immunol. 2013 May;131(5):1376-83.e3
references: 23561803
references: Hum Immunol. 2013 Oct;74(10):1271-9
references: 23770250
references: Science. 2003 Nov 28;302(5650):1581-4
references: 14576442
references: Trends Immunol. 2003 Aug;24(8):419-24
references: 12909454
references: Proc Natl Acad Sci U S A. 2004 Mar 30;101(13):4566-71
references: 15070758
references: Mol Cell. 2013 Sep 26;51(6):766-79
references: 24074955
references: EMBO J. 2007 Nov 14;26(22):4634-45
references: 17948050
references: Blood. 2009 Oct 22;114(17):3524-32
references: 19638621
references: J Clin Invest. 2004 Nov;114(10):1409-11
references: 15545990
references: Curr Opin Cell Biol. 1997 Jun;9(3):420-9
references: 9159083
references: J Immunol. 2009 Jun 1;182(11):6736-43
references: 19454668
references: N Engl J Med. 2013 Dec 26;369(26):2504-14
references: 24369075
references: Immunity. 2003 Nov;19(5):749-58
references: 14614861
references: Blood. 2005 Dec 15;106(13):4210-6
references: 16123224
references: Cold Spring Harb Perspect Biol. 2010 Sep;2(9):a003004
references: 20685844
references: Mol Cell. 2004 May 7;14(3):289-301
references: 15125833
references: Annu Rev Immunol. 1998;16:225-60
references: 9597130
references: J Allergy Clin Immunol. 2014 May;133(5):1458-62, 1462.e1-7
references: 24332264
references: Genome Res. 2010 Sep;20(9):1297-303
references: 20644199
references: Am J Hum Genet. 2000 Dec;67(6):1555-62
references: 11047757
references: J Clin Immunol. 2013 Apr;33(3):540-9
references: 23264026
references: J Clin Invest. 2003 Oct;112(7):983-5
references: 14523034
references: J Allergy Clin Immunol. 2013 Jul;132(1):151-8
references: 23727036
references: J Allergy Clin Immunol. 2013 Feb;131(2):477-85.e1
references: 23374270
references: Proc Natl Acad Sci U S A. 2011 Dec 27;108(52):21004-9
references: 22158899
references: Nat Immunol. 2007 Sep;8(9):984-91
references: 17660823
references: Nat Genet. 2011 May;43(5):491-8
references: 21478889
references: J Allergy Clin Immunol. 2005 Feb;115(2):391-8
references: 15696101
references: Immunodefic Rev. 1989;1(2):135-53
references: 2517209
references: Tissue Antigens. 1998 Oct;52(4):393-6
references: 9820605
references: Immunol Rev. 2003 Jun;193:93-100
references: 12752674
references: Nat Rev Cancer. 2004 Feb;4(2):106-17
references: 14732865
references: Fly (Austin). 2012 Apr-Jun;6(2):80-92
references: 22728672
references: J Allergy Clin Immunol. 2014 Aug;134(2):276-84
references: 25087226
references: Oncogene. 2003 Nov 6;22(50):8085-92
references: 14603249
references: Nature. 2004 Jan 8;427(6970):167-71
references: 14695475
references: Immunol Rev. 2009 Sep;231(1):189-209
references: 19754898
references: Bioinformatics. 2009 Jul 15;25(14):1754-60
references: 19451168
references: Transplantation. 2005 May 15;79(9):1268-72
references: 15880083
references: Front Immunol. 2014 Apr 22;5:162
references: 24795713
references: Nat Rev Immunol. 2004 May;4(5):348-59
references: 15122200