ABSTRACT
Common variable immunodeficiency (CVID) is considered the most common symptomatic antibody deficiency and, although mainly reported in adults, it may present from childhood. Few data on the impact of TACI defects on the clinical and immunological status of children are available. We screened 42 hypogammaglobulinemic children to investigate the frequency and mutational features of TACI defects. The genetic, clinical and immunological characterization was extended to 31 relatives of 11 children with TACI mutations. Of interest, our analysis showed a considerably higher mutation frequency in hypogammaglobulinemic children (13/42; 31%) than in other cohorts of adult patients. In seven out of nine families with the C104R variant, the prevalence of autoimmunity was significantly higher in C104R heterozygous relatives (8/15; 53%) than in those with no C104R mutation (1/11; 9%). Our data suggest a different impact of TACI mutations, from hypogammaglobulinemia in children to autoimmune disease in adulthood.
Subject(s)
Agammaglobulinemia/genetics , Agammaglobulinemia/immunology , Autoimmunity/genetics , Common Variable Immunodeficiency/genetics , Common Variable Immunodeficiency/immunology , Mutation , Transmembrane Activator and CAML Interactor Protein/genetics , Adolescent , Adult , Age Factors , Aged , Aging/genetics , Aging/immunology , Case-Control Studies , Child , Child, Preschool , Female , Gene Frequency , Genetic Predisposition to Disease , Heterozygote , Homozygote , Humans , Italy , Male , Middle Aged , Pedigree , Phenotype , Young AdultABSTRACT
Deletions of chromosome 22q11.2 have been associated with distinct phenotypes including DiGeorge syndrome (DGS) and velo-cardio-facial (VCFS) syndrome. These diseases result from a failure to form derivatives of the third and fourth branchial arches during development. DGS/VCFS deletions usually encompass about 3 Mb of genomic DNA in more than 90% of patients. However, deletion mapping studies have failed to demonstrate the existence of a single small region of overlap (SRO) and ruled out any obvious correlation between site or size of deletion and severity of clinical phenotype. We describe three patients carrying 'atypical' deletions presenting the DGS/VCFS phenotype. A comparative analysis of deletions in our patients and those previously published has suggested the existence of five distinct critical regions within the 22q11.2 locus. This observation argues that DGS/VCFS results from haploinsufficiency secondary to a complex and as yet unexplained molecular mechanism, probably involving chromatin effects in mediating gene expression throughout the entire region.
Subject(s)
Chromosomes, Human, Pair 22 , DiGeorge Syndrome/genetics , Gene Deletion , Child, Preschool , Face/abnormalities , Female , Heart Defects, Congenital/genetics , Humans , In Situ Hybridization, Fluorescence , Infant , Intellectual Disability/genetics , Karyotyping , Male , PhenotypeABSTRACT
We have isolated a few cDNAs from different human tissues, transcribed from the first intron of HIRA, a gene deleted in the DiGeorge syndrome. These cDNAs are produced by an intronic gene (22k48) which is transcribed by the HIRA opposite strand and is itself arranged in exons and subjected to alternative splicing. The longest continuum cDNA sequence we obtained is 3.6 kb long and contains 3 different exons and 2 introns. 22k48 cDNA is composed of several tandemly arranged repeated elements (Alu, LINEs, CAn) surrounding a unique sequence. In situ hybridization showed the presence of 22k48 RNA in the cytoplasm of CNS and PNS neurons. 22k48 RNA is able to bind cytoplasmic proteins in the range of 45 to 60 kDa. 22k48 is a new member of the small group of genes that are transcribed but not translated, and its haploinsufficiency could contribute to the pathogenesis of the DiGeorge syndrome.
Subject(s)
Cell Cycle Proteins , Chromosomes, Human, Pair 22 , DiGeorge Syndrome/genetics , Nuclear Proteins/genetics , RNA, Messenger/metabolism , Transcription Factors/genetics , Transcription, Genetic , Adult , Alternative Splicing , Blotting, Northern , Chromosomes, Artificial, Yeast , Cloning, Molecular , Cytoplasm/metabolism , DNA, Complementary , Female , Histone Chaperones , Humans , In Situ Hybridization , Introns , Microsatellite Repeats , Neurons/metabolism , Pregnancy , RNA, Messenger/genetics , RNA-Binding Proteins/metabolismABSTRACT
We report the genomic organization, RNA and protein expression patterns of the gene encoding for the human homolog of the yeast ubiquitin fusion-degradation protein-1 (UFD1L). This enzyme is involved in a ubiquitin-dependent proteolytic pathway (UFD), firstly described in yeast. The human UFD1L gene is organized into 12 exons ranging in size from 33 to 161 bp. Sequence analysis of the 5'-flanking region of the gene revealed a high GC content, multiple CCAAT-binding motifs, CREB, CFT, and AP-2 sites. RNA transcripts were detected in all tissues and cell lines examined, including thymus, thymocytes, T- and B-cells, fibroblasts, chorionic villi, and amniocytes. In Western blot, the UFD1L antibody demonstrated the presence of multiple protein isoforms in all the tested tissues. Expression profile and promoter characteristics suggest UFD1L is a housekeeping gene with implications in the pathogenesis of DiGeorge/velo-cardio-facial syndrome, due to 22q11.2 deletions.
