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16 results on '"Peter, Mustillo"'

5. Somatic reversion in dedicator of cytokinesis 8 immunodeficiency modulates disease phenotype

Author

Alexandra F. Freeman, Yu Zhang, Helen F. Matthews, Peter Mustillo, Christopher G. Dove, Fotini D Kavadas, Huie Jing, Raif S. Geha, Brenna J. Hill, David B. Lewis, Steven M. Holland, Ashish R Kumar, Erwin W. Gelfand, I. Celine Hanson, Gulbu Uzel, Qian Zhang, T. Prescott Atkinson, Daniel C. Douek, and Helen C. Su

Subjects
Adolescent, DNA Repair, Genotype, Somatic cell, DNA repair, T-Lymphocytes, DNA Mutational Analysis, Immunology, B-Lymphocyte Subsets, Biology, medicine.disease_cause, Article, Immunophenotyping, Germline mutation, T-Lymphocyte Subsets, medicine, Guanine Nucleotide Exchange Factors, Humans, Immunology and Allergy, Child, Germ-Line Mutation, Immunodeficiency, Mutation, Immunologic Deficiency Syndromes, medicine.disease, Killer Cells, Natural, Transplantation, Phenotype, Child, Preschool, Dock8, DOCK8 Deficiency
Abstract

Background Autosomal recessive loss-of-function mutations in dedicator of cytokinesis 8 (DOCK8) cause a combined immunodeficiency characterized by atopy, recurrent infections, and cancer susceptibility. A genotype-phenotype explanation for the variable disease expression is lacking. Objective We investigated whether reversions contributed to the variable disease expression. Methods Patients followed at the National Institutes of Health's Clinical Center were studied. We performed detailed genetic analyses and intracellular flow cytometry to detect DOCK8 protein expression within lymphocyte subsets. Results We identified 17 of 34 DOCK8-deficient patients who had germline mutations with variable degrees of reversion caused by somatic repair. Somatic repair of the DOCK8 mutations resulted from second-site mutation, original-site mutation, gene conversion, and intragenic crossover. Higher degrees of reversion were associated with recombination-mediated repair. DOCK8 expression was restored primarily within antigen-experienced T cells or natural killer cells but less so in naive T or B cells. Several patients exhibited multiple different repair events. Patients who had reversions were older and had less severe allergic disease, although infection susceptibility persisted. No patients were cured without hematopoietic cell transplantation. Conclusions In patients with DOCK8 deficiency, only certain combinations of germline mutations supported secondary somatic repair. Those patients had an ameliorated disease course with longer survival but still had fatal complications or required hematopoietic cell transplantation. These observations support the concept that some DOCK8-immunodeficient patients have mutable mosaic genomes that can modulate disease phenotype over time.

Published
2014
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6. Screening for Severe Combined Immunodeficiency on the Ohio Newborn Screen Using TREC Analysis: Experience from the First Four Years

Author

David E. Tapke, Benjamin Prince, Rebecca A. Marsh, Rebecca Scherzer, Nancy Wasserbauer, Leigh Ann A. Kerns, Peter Mustillo, Kimberly A. Risma, Sherman J. Alter, Rosemary Hage, and Sharon Linard

Subjects
0301 basic medicine, Severe combined immunodeficiency, Pediatrics, medicine.medical_specialty, business.industry, Immunology, medicine.disease, 03 medical and health sciences, 030104 developmental biology, 0302 clinical medicine, medicine, Immunology and Allergy, business, 030215 immunology
Published
2018
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10. Newborn Screening for Severe Combined Immunodeficiency (SCID) in Ohio: Using Algorithms to Standardize Follow-up Limits the Number of False Positive Results

Author

Ram Chandrasekar, Nancy Wasserbauer, Alexandra H. Filipovich, Velma Paschall, Sherman J. Alter, Rebecca Scherzer, Leigh Ann A. Kerns, Sharon Linard, Peter Mustillo, Kimberly A. Risma, Rebecca A. Marsh, Jack J. Bleesing, and Rosemary Hage

Subjects
Pediatrics, medicine.medical_specialty, Severe combined immunodeficiency, Newborn screening, business.industry, Immunology, medicine, Immunology and Allergy, business, medicine.disease
Published
2015
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