Lack of IL7Rα expression in T cells is a hallmark of T-cell immunodeficiency in Schimke immuno-osseous dysplasia (SIOD).
Schimke immuno-osseous dysplasia (SIOD) is an autosomal recessive, fatal childhood disorder associated with skeletal dysplasia, renal dysfunction, and T-cell immunodeficiency. This disease is linked to biallelic loss-of-function mutations of the SMARCAL1 gene. Although recurrent infection, due to T-cell deficiency, is a leading cause of morbidity and mortality, the etiology of the T-cell immunodeficiency is unclear. Here, we demonstrate that the T cells of SIOD patients have undetectable levels of protein and mRNA for the IL-7 receptor alpha chain (IL7Rα) and are unresponsive to stimulation with IL-7, indicating a loss of functional receptor. No pathogenic mutations were detected in the exons of IL7R in these patients; however, CpG sites in the IL7R promoter were hypermethylated in SIOD T cells. We propose therefore that the lack of IL7Rα expression, associated with hypermethylation of the IL7R promoter, in T cells and possibly their earlier progenitors, restricts T-cell development in SIOD patients.
Department of Medicine, Stanford University School of Medicine, Stanford, CA, USA; Department of Pathology, Stanford University School of Medicine, Stanford, CA, USA. Electronic address: msanyal@stanford.edu.
Mrinmoy
M
Sanyal
Department of Medical Genetics and Child and Family Research Institute, University of British Columbia, Vancouver, BC, Canada.
Marie
M
Morimoto
Department of Biochemistry and Molecular Biology, University of British Columbia, Vancouver, BC, Canada.
Alireza
A
Baradaran-Heravi
Department of Medical Genetics and Child and Family Research Institute, University of British Columbia, Vancouver, BC, Canada.
Kunho
K
Choi
Department of Pathology, Stanford University School of Medicine, Stanford, CA, USA.
Neeraja
N
Kambham
Department of Medicine, Division of Rheumatology and Immunology, Stanford University School of Medicine, Stanford, CA, USA.
Kent
K
Jensen
Department of Medicine, Division of Rheumatology and Immunology, Stanford University School of Medicine, Stanford, CA, USA.
Suparna
S
Dutt
Department of Pediatrics, Division of Allergy, Immunology, and Rheumatology, Stanford University School of Medicine, Stanford, CA, USA.
Kira Y
KY
Dionis-Petersen
Department of Pediatrics, Division of Allergy, Immunology, and Rheumatology, Stanford University School of Medicine, Stanford, CA, USA.
Lan Xiang
LX
Liu
Department of Cardiothoracic Surgery, Division of Pediatric Cardiothoracic Surgery, Lucile Packard Children's Hospital at Stanford, Stanford, CA, USA.
Katie
K
Felix
Warren Clinic, Tulsa, OK, USA.
Christy
C
Mayfield
Pediatric Stem Cell Research Institute, Safra Children's Hospital, Sheba Medical Center, Sackler School of Medicine, Tel Aviv, Israel.
Benjamin
B
Dekel
Department of Pediatric Nephrology, VU University Medical Center, Amsterdam, The Netherlands.
Arend
A
Bokenkamp
Department of Medical Genetics, "Aghia Sophia" Children's Hospital, Athens University Medical School, Athens, Greece.
Helen
H
Fryssira
Sección de Genética Médica, Servicio de Pediatría, Hospital Clínico Universitario Virgen de la Arrixaca, IMIB-Arrixaca, Murcia, Spain; UCAM-Universidad Católica de Murcia, Spain; CIBERER-ISCIII, Madrid, Spain.
Encarna
E
Guillen-Navarro
Department of Pediatrics, University of Naples, Naples, Italy.
Giuliana
G
Lama
Department of Pediatrics, University of Verona, Verona, Italy.
Milena
M
Brugnara
Department of Neuropediatrics, Children's Hospital, Ruhr-University Bochum, Bochum, Germany.
Thomas
T
Lücke
Department of Pediatrics, University of Nebraska Medical Center, Omaha, NE, USA.
Ann Haskins
AH
Olney
Division of Pediatric Nephrology, Vanderbilt Children's Hospital, Nashville, TN, USA.
Tracy E
TE
Hunley
Department of Pediatrics, Dokuz Eylul University, Izmir, Turkey.
Ayse Ipek
AI
Polat
Department of Pediatrics, Dokuz Eylul University, Izmir, Turkey.
Uluc
U
Yis
Institute of Mother and Child Health Care of Serbia and Faculty of Medicine, University of Belgrade, Belgrade, Serbia.
Radovan
R
Bogdanovic
Institute of Mother and Child Health Care of Serbia and Faculty of Medicine, University of Belgrade, Belgrade, Serbia.
Katarina
K
Mitrovic
Department of Pediatrics, University of Minnesota Health System, Minneapolis, MN, USA.
Susan
S
Berry
Department of Pediatrics, University of Minnesota Health System, Minneapolis, MN, USA.
Lydia
L
Najera
Department of Pathology, University of Washington, Seattle, WA, USA.
Behzad
B
Najafian
Department of Medical Genetics, Hospital Di Venere - ASL Bari, Bari, Italy.
Mattia
M
Gentile
Department of Medical Genetics, School of Medicine, Pamukkale University, Denizli, Turkey.
C
C
Nur Semerci
Pediatric Multidisciplinary Unit, AP-HM Timone Enfant, Aix-Marseille University, Marseille, France.
Michel
M
Tsimaratos
Department of Pediatrics, Division of Allergy, Immunology, and Rheumatology, Stanford University School of Medicine, Stanford, CA, USA.
David B
DB
Lewis
Department of Medical Genetics and Child and Family Research Institute, University of British Columbia, Vancouver, BC, Canada. Electronic address: boerkoel@interchange.ubc.ca.
Cornelius F
CF
Boerkoel
D000293:Adolescent; D000328:Adult; D001161:Arteriosclerosis / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D002478:Cells, Cultured; D002648:Child; D002675:Child, Preschool; D004265:DNA Helicases / Q000235:genetics; D019175:DNA Methylation; D005434:Flow Cytometry; D015870:Gene Expression; D006801:Humans; D007150:Immunohistochemistry; D007153:Immunologic Deficiency Syndromes / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D020381:Interleukin-17 / Q000494:pharmacology; D007963:Leukocytes, Mononuclear / Q000187:drug effects / Q000378:metabolism; D009154:Mutation; D009404:Nephrotic Syndrome / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D010009:Osteochondrodysplasias / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D000081207:Primary Immunodeficiency Diseases; D011401:Promoter Regions, Genetic / Q000235:genetics; D011655:Pulmonary Embolism / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D020395:Receptors, Interleukin-7 / Q000235:genetics* / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D017422:Sequence Analysis, DNA; D013601:T-Lymphocytes / Q000378:metabolism*; D055815:Young Adult
D020381:Interleukin-17; D020395:Receptors, Interleukin-7; C415350:interleukin-7 receptor, alpha chain; C412482:SMARCAL1 protein, human; D004265:DNA Helicases
CD127; CpG; IL7Rα; Promoter DNA methylation; SIOD; T-cell immunodeficiency