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J Clin Invest ; 127(12): 4415-4420, 2017 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-29106381


Primary immunodeficiencies are often monogenic disorders characterized by vulnerability to specific infectious pathogens. Here, we performed whole-exome sequencing of a patient with disseminated Mycobacterium abscessus, Streptococcus viridians bacteremia, and cytomegalovirus (CMV) viremia and identified mutations in 2 genes that regulate distinct IFN pathways. The patient had a homozygous frameshift deletion in IFNGR2, which encodes the signal transducing chain of the IFN-γ receptor, that resulted in minimal protein expression and abolished downstream signaling. The patient also harbored a homozygous deletion in IFNAR1 (IFNAR1*557Gluext*46), which encodes the IFN-α receptor signaling subunit. The IFNAR1*557Gluext*46 resulted in replacement of the stop codon with 46 additional codons at the C-terminus. The level of IFNAR1*557Gluext*46 mutant protein expressed in patient fibroblasts was comparable to levels of WT IFNAR1 in control fibroblasts. IFN-α-induced signaling was impaired in the patient fibroblasts, as evidenced by decreased STAT1/STAT2 phosphorylation, nuclear translocation of STAT1, and expression of IFN-α-stimulated genes critical for CMV immunity. Pretreatment with IFN-α failed to suppress CMV protein expression in patient fibroblasts, whereas expression of WT IFNAR1 restored IFN-α-mediated suppression of CMV. This study identifies a human IFNAR1 mutation and describes a digenic immunodeficiency specific to type I and type II IFNs.

Hum Mutat ; 38(10): 1355-1359, 2017 10.
Artigo em Inglês | MEDLINE | ID: mdl-28585352


Griscelli syndrome type 2 (GS2) is a rare and often fatal autosomal recessive, hyperinflammatory disorder. It is associated with hypopigmentation of the skin and the hair, resulting in the characteristic pigment accumulation and clumping in the hair shaft. Loss-of-function mutations in RAB27A, resulting from point mutations, short indel, or large deletions, account for all the cases reported to date. However, several GS2 cases originating from Saudi Arabia lack a genetic diagnosis. Here, we report on a new RAB27A genetic anomaly observed in seven Saudi Arabia families that had remained negative after extensive molecular genomic DNA testing. Linkage analysis and targeted sequencing of the RAB27A genomic region in several of these patients led to the identification of a common homozygous tandem duplication of 38 kb affecting exon 2-5 and resulting in a premature stop codon. The pathogenic effect of this duplication was confirmed by a cDNA analysis and functional assays. The identification of microhomology flanking the breakpoint site suggests a possible underlying mechanism.

Hipopigmentação/diagnóstico , Hipopigmentação/genética , Síndromes de Imunodeficiência/diagnóstico , Síndromes de Imunodeficiência/genética , Linfo-Histiocitose Hemofagocítica/diagnóstico , Linfo-Histiocitose Hemofagocítica/genética , Piebaldismo/diagnóstico , Piebaldismo/genética , Proteínas rab27 de Ligação ao GTP/genética , Códon sem Sentido , Consanguinidade , Éxons/genética , Feminino , Duplicação Gênica/genética , Ligação Genética , Cabelo/patologia , Homozigoto , Humanos , Hipopigmentação/metabolismo , Hipopigmentação/patologia , Síndromes de Imunodeficiência/patologia , Linfo-Histiocitose Hemofagocítica/patologia , Masculino , Mutação/genética , Linhagem , Piebaldismo/patologia , Arábia Saudita , Deleção de Sequência , Pigmentação da Pele/genética , Linfócitos T Citotóxicos/patologia
Pediatr Blood Cancer ; 51(2): 295-8, 2008 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-18454469


Subdural fluid collections can interfere with the effective intrathecal administration of chemotherapy by lumbar puncture (LP). We detected this complication in six children who were treated for acute lymphoblastic leukemia (ALL) and presented with an elevated protein concentration of the cerebrospinal fluid (CSF) during routine LP. Contrary to expectation the lumbar fluid collections persisted in two cases and in one case required the insertion of an Ommaya reservoir to continue intrathecal chemotherapy. Awareness and detection of this complication by imaging is important because of its potential to interfere with effective CNS-directed chemotherapy of ALL.

Antineoplásicos/administração & dosagem , Proteínas do Líquido Cefalorraquidiano/análise , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Punção Espinal/efeitos adversos , Pré-Escolar , Feminino , Humanos , Lactente , Injeções Espinhais , Masculino , Leucemia-Linfoma Linfoblástico de Células Precursoras/líquido cefalorraquidiano