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1.  Stem-Cell Gene Therapy for the Wiskott–Aldrich Syndrome 
The New England journal of medicine  2010;363(20):1918-1927.
The Wiskott–Aldrich syndrome (WAS) is an X-linked recessive primary immunodeficiency disorder associated with thrombocytopenia, eczema, and autoimmunity. We treated two patients who had this disorder with a transfusion of autologous, genetically modified hematopoietic stem cells (HSC). We found sustained expression of WAS protein expression in HSC, lymphoid and myeloid cells, and platelets after gene therapy. T and B cells, natural killer (NK) cells, and monocytes were functionally corrected. After treatment, the patients’ clinical condition markedly improved, with resolution of hemorrhagic diathesis, eczema, autoimmunity, and predisposition to severe infection. Comprehensive insertion-site analysis showed vector integration that targeted multiple genes controlling growth and immunologic responses in a persistently polyclonal hematopoiesis. (Funded by Deutsche Forschungsgemeinschaft and others; German Clinical Trials Register number, DRKS00000330.)
PMCID: PMC3064520  PMID: 21067383
2.  Inflammatory Bowel Disease and Mutations Affecting the Interleukin-10 Receptor 
The New England journal of medicine  2009;361(21):2033-2045.
The molecular cause of inflammatory bowel disease is largely unknown.
We performed genetic-linkage analysis and candidate-gene sequencing on samples from two unrelated consanguineous families with children who were affected by early-onset inflammatory bowel disease. We screened six additional patients with early-onset colitis for mutations in two candidate genes and carried out functional assays in patients’ peripheral-blood mononuclear cells. We performed an allogeneic hematopoietic stem-cell transplantation in one patient.
In four of nine patients with early-onset colitis, we identified three distinct homozygous mutations in genes IL10RA and IL10RB, encoding the IL10R1 and IL10R2 proteins, respectively, which form a heterotetramer to make up the interleukin-10 receptor. The mutations abrogate interleukin-10–induced signaling, as shown by deficient STAT3 (signal transducer and activator of transcription 3) phosphorylation on stimulation with interleukin-10. Consistent with this observation was the increased secretion of tumor necrosis factor α and other proinflammatory cytokines from peripheral-blood mononuclear cells from patients who were deficient in IL10R subunit proteins, suggesting that interleukin-10–dependent “negative feedback” regulation is disrupted in these cells. The allogeneic stem-cell transplantation performed in one patient was successful.
Mutations in genes encoding the IL10R subunit proteins were found in patients with early-onset enterocolitis, involving hyperinflammatory immune responses in the intestine. Allogeneic stem-cell transplantation resulted in disease remission in one patient.
PMCID: PMC2787406  PMID: 19890111
3.  A novel syndrome with congenital neutropenia caused by mutations in G6PC3 
Severe congenital neutropenia (SCN) is characterized by early onset of severe bacterial infections due to a paucity of mature neutrophils. There is also an increased risk of leukemia. The genetic causes of SCN are unknown in many patients.
Genome-wide genotyping and linkage analysis were performed on two consanguineous pedigrees with a total of five children affected with SCN. Candidate genes from the linkage interval were sequenced. Functional assays and reconstitution experiments were carried out.
All index patients had susceptibility to bacterial infections and myeloid maturation arrest in the bone marrow; some had structural heart defects and venous angiectasia on the trunk and extremities. Linkage analysis of the two index families yielded a combined multipoint LOD score of 5.74 on a linkage interval on chromosome 17q21. Sequencing of the candidate gene glucose-6-phosphatase catalytic subunit 3 (G6PC3) revealed a homozygous missense mutation in exon 6 in all affected children in the two families, abrogating enzymatic activity of Glucose-6-phosphatase. Neutrophils and fibroblasts of patients had increased susceptibility to apoptosis. Myeloid cells showed evidence of increased endoplasmic reticulum stress and increased activity of GSK3β. We identified seven additional, unrelated SCN patients with syndromic features and distinct biallelic mutations in G6PC3.
Defective function of G6PC3 defines a novel SCN syndrome associated with cardiac and urogenital malformations.
PMCID: PMC2778311  PMID: 19118303

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