Identification of missense mutation in BCL11B; immune deficit in infant corrected with HSCT
THURSDAY, Dec. 1, 2016 (HealthDay News) — Mutant BCL11B has been identified as a cause of severe combined immunodeficiency (SCID) in newborn screening, according to a study published in the Dec. 1 issue of the New England Journal of Medicine.
Divya Punwani, Ph.D., from the University of California in San Francisco, and colleagues detected SCID in a newborn before onset of infections using screening of T-cell-receptor excision circles. The affected infant was treated with allogeneic hematopoietic stem-cell transplantation on confirmation of the condition. Following exome sequencing in the patient and parents, they conducted a functional analysis of a prioritized candidate gene using hematopoietic stem cells and zebrafish embryos.
The researchers found that the infant had “leaky” SCID, with preservation of a minimal degree of immune function, craniofacial and dermal abnormalities, and absence of a corpus callosum. Hematopoietic stem-cell transplantation fully corrected his immune deficit. A heterozygous de novo missense mutation, p.N441K, in BCL11B was identified in exome sequencing. The resulting protein had dominant negative activity, which prevented the wild-type protein from binding DNA, thereby arresting T-cell lineage development and disrupting hematopoietic stem-cell migration. When recapitulated in bcl11ba-deficient zebrafish, the patient’s abnormalities were reversed by ectopic expression of functionally intact, but not mutant, human BCL11B.
“Newborn screening facilitated the identification and treatment of a previously unknown cause of human SCID,” the authors write.
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