Carrier Frequency of a Nonsense Mutation in the Adenosine Deaminase (ADA) Gene Implies a High Incidence of ADA‐deficient Severe Combined Immunodeficiency (SCID) in Somalia and a Single, Common Haplotype Indicates Common Ancestry

@article{Snchez2007CarrierFO,
  title={Carrier Frequency of a Nonsense Mutation in the Adenosine Deaminase (ADA) Gene Implies a High Incidence of ADA‐deficient Severe Combined Immunodeficiency (SCID) in Somalia and a Single, Common Haplotype Indicates Common Ancestry},
  author={Juan Jos{\'e} Garc{\'i}a S{\'a}nchez and Gemma Monaghan and Claus B{\o}rsting and Gail Norbury and Niels Morling and H. Bobby Gaspar},
  journal={Annals of Human Genetics},
  year={2007},
  volume={71}
}
Inherited adenosine deaminase (ADA) deficiency is a rare metabolic disorder that causes immunodeficiency, varying from severe combined immunodeficiency (SCID) in the majority of cases to a less severe form in a small minority of patients. Five patients of Somali origin from four unrelated families, with severe ADA‐SCID, were registered in the Greater London area. Patients and their parents were investigated for the nonsense mutation Q3X (ADA c7C>T), two missense mutations K80R (ADA c239A>G) and… 
Genetic and biochemical consequences of adenosine deaminase deficiency in humans.
TLDR
Tandem mass spectrometry coupled with high efficiency separation systems enables postnatal diagnosis of the disorder, while prenatal diagnosis relies on assaying enzyme activity in cultured amniotic fibroblasts or chorionic villi sampling, and screening of adenosine deaminase deficiency for relatives-at-risk may reduce costs of treatment and ensure timely medical intervention.
A 475 years-old founder effect involving IL12RB1: a highly prevalent mutation conferring Mendelian Susceptibility to Mycobacterial Diseases in European descendants.
  • J. Yancoski, C. Rocco, S. Rosenzweig
  • Biology
    Infection, genetics and evolution : journal of molecular epidemiology and evolutionary genetics in infectious diseases
  • 2009
Severe combined immunodeficiency—a purine metabolism disorder
TLDR
While previously diagnosed based on recurrent, severe, or unusual infection, SCID is now being diagnosed during its initial asymptomatic period thanks to recent implementation of T cell receptor excision circle (TREC) newborn screening, thus greatly improving survival of patients as treatment can occur before the onset of infection.
Recent advances in understanding and managing adenosine deaminase and purine nucleoside phosphorylase deficiencies
TLDR
Newborn screening and early diagnosis will allow prompt application of novel treatment strategies, further improving survival and reducing morbidity, and better understanding of the complex immune and nonimmune effects of ADA and PNP deficiency holds great promise for improved patients’ outcome.
Genome-wide analyses disclose the distinctive HLA architecture and the pharmacogenetic landscape of the Somali population
TLDR
The Somali population displays genetic traits of significance to health and disease, and ethnic Somalis were found to host the highest frequencies observed thus far for several pharmacogenetic variants, including UGT1A4*2.
Role of DNA repair in class switch recombination and somatic hypermutation
TLDR
The data suggest that the role of ATR is partially overlapping with ATM, whereas Ataxiatelangiectasia and Rad3-related (ATR), Artemis, Cernunnos and the Mre11-Rad50-NBS1 (MRN) complex, CSR junctions and SHM patterns in the immunoglobulin variable region gene were analyzed in patients with deficiency in these factors.
...
...

References

SHOWING 1-10 OF 54 REFERENCES
Three new adenosine deaminase mutations that define a splicing enhancer and cause severe and partial phenotypes: implications for evolution of a CpG hotspot and expression of a transduced ADA cDNA.
TLDR
The severe and healthy phenotypes associated with R142X and R142Q, the high frequency of 'partial' ADA mutations arising from CpGs in healthy individuals of African descent and the presence of CAA (glutamine) at codon 142 in murine ADA, suggest selection for replacement of this CpG hotspot by CpA during ADA evolution.
An Asp8Asn substitution results in the adenosine deaminase (ADA) genetic polymorphism (ADA 2 allozyme): occurrence on different chromosomal backgrounds and apparent intragenic crossover
TLDR
The molecular genetic basis for the common biochemical polymorphism at the adenosine deaminase (ADA) locus is determined and a probable intragenic crossover in the very large first intron that is rich in repetitive DNA sequences is identified.
Adenosine deaminase (ADA) deficiency in cells derived from humans with severe combined immunodeficiency is due to an aberration of the ADA protein.
TLDR
The results indicate that in these two ADA-SCID cell lines, the lack of ADA activity is not due to transcriptional or translational defects, but to subtle changes in the configuration of the protein affecting both its enzymatic and immunological characteristics.
One adenosine deaminase allele in a patient with severe combined immunodeficiency contains a point mutation abolishing enzyme activity.
TLDR
Cloned and sequenced an adenosine deaminase gene from a patient with severe combined immunodeficiency (SCID) caused by inherited ADA deficiency showed that the mutation at position 304 is responsible for ADA inactivation.
Nucleotide pool imbalance and adenosine deaminase deficiency induce alterations of N-region insertions during V(D)J recombination.
TLDR
It is concluded that the frequency of V(D)J recombination and the composition of N-insertions are influenced by increases in dATP levels, potentially leading to alterations in antigen receptors and aberrant lymphoid development.
Genotype is an important determinant of phenotype in adenosine deaminase deficiency.
Somatic cell genetics of adenosine deaminase expression and severe combined immunodeficiency disease in humans.
  • G. Koch, T. Shows
  • Biology
    Proceedings of the National Academy of Sciences of the United States of America
  • 1980
TLDR
Genetic and biochemical characterization of ADA in SCID and the ADA tissue-specific isozymes in normal human cells indicates that additional genes, besides the ADA structural gene on chromosome 20, are involved in ADA expression, and it is proposed that the expression of the polymeric ADA tissue isoz enzymes in human cells requires at least three genes.
PEG‐ADA: An alternative to haploidentical bone marrow transplantation and an adjunct to gene therapy for adenosine deaminase deficiency
TLDR
PEG‐ADA is a long‐circulating form of adenosine deaminase that has been in use for <8 years as replacement therapy for severe combined immunodeficiency disease due to ADA deficiency, although its continued use poses a problem for evaluation of the benefit of gene therapy.
Clustered Charged Amino Acids of Human Adenosine Deaminase Comprise a Functional Epitope for Binding the Adenosine Deaminase Complexing Protein CD26/Dipeptidyl Peptidase IV*
Human adenosine deaminase (ADA) occurs as a 41-kDa soluble monomer in all cells. On epithelia and lymphoid cells of humans, but not mice, ADA also occurs bound to the membrane glycoprotein
...
...