Severe combined immune deficiency due to a homozygous 3.2-kb deletion spanning the promoter and first exon of the adenosine deaminase gene

Berkvens, Th.M.; Gerritsen, E. J. A.; Oldenburg, M.; Breukel, Cor; Wijnen, Juul T.; Ormondt, H. van; Vossen, Jaak M.; Eb, A. J. Van Der; Khan, P. Meera

doi:10.1093/nar/15.22.9365

Cited by 32 publications

(17 citation statements)

References 27 publications

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“…The size of the d'20" deletion (3,580 nucleotides) and the absence of terminal sequence homology are inconsistent with a direct error by DNA polymerase generating this deletion, as has been described for both procaryotic and eucaryotic deletions (1,9,22). Furthermore, the unique sequence of the DNA flanking the deletion termini appears to rule out an uneven crossing over between repetitive genomic elements, as suggested for spontaneous deletions in human P-globin, low-density lipoprotein receptor, adenosine deaminase, and growth hormone genes (3,5,28,38).…”

Section: Discussionmentioning

confidence: 92%

Molecular analysis of two mouse dilute locus deletion mutations: spontaneous dilute lethal20J and radiation-induced dilute prenatal lethal Aa2 alleles.

et al. 1990

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The dilute (d) coat color locus of mouse chromosome 9 has been identified by more than 200 spontaneous and mutagen-induced recessive mutations. With the advent of molecular probes for this locus, the molecular lesion associated with different dilute alleles can be recognized and precisely defined. In this study, two dilute mutations, dilute-lethal20' (d'a01) and dilute prenatal lethal Aa2, have been examined. Using a dilute locus genomic probe in Southern blot analysis, we detected unique restriction fragments in de0J and Aa2 DNA.Subsequent analysis of these fragments showed that they represented deletion breakpoint fusion fragments. DNA sequence analysis of each mutation-associated deletion breakpoint fusion fragment suggests that both genomic deletions were generated by nonhomologous recombination events. The spontaneous dL'OJ mutation is caused by an interstitial deletion that removes a single coding exon of the dilute gene. The correlation between this discrete deletion and the expression of all dilute-associated phenotypes in F0I homozygotes defines the d"P0 mutation as a functional null allele of the dilute gene. The radiation-induced Aa2 allele is a multilocus deletion that, by complementation analysis, affects both the dilute locus and the proximal prenatal lethal-3 (p1-3) functional unit. Molecular analysis of the Aa2 deletion breakpoint fusion fragment has provided access to a previously undefined gene proximal to d. Initial characterization of this new gene suggests that it may represent the genetically defined pl-3 functional unit.Classic genetic analysis of variant mouse phenotypes has defined numerous genetic loci and, in some cases, numerous alleles at a given locus. However, the physical basis for these mutations and an understanding of the impact of mutagenic events on gene expression have been impeded by difficulties in gaining molecular access to the mutated genes. The murine dilute (d) locus is among those rare loci for which extensive analysis at both the genetic and molecular levels is possible. A vast collection of spontaneous, chemical-induced, and radiation-induced dilute locus mutations have been generated. With the ever-increasing number of genomic and cDNA probes for the dilute locus, the physical detection and precise analysis of DNA alterations and rearrangements associated with individual d alleles can now be accomplished. As illustrated in this study, this combined molecular and genetic analysis is elucidating the gene product(s) and genomic organization not only of the d locus but also of other loci in the d region of mouse chromosome 9.More than 200 spontaneous and induced dilute mutations have been identified (25 duced dilute-opisthotonic (d0P) class exhibit the neurological disorder of opisthotonus, a convulsive arching of the animal's head and neck (30,33,34). These seizures are readily apparent at 9 days postpartum and continue until death at approximately 3 weeks of age. In extensive complementation analysis, the coat color, opisthotonic, and lethality phenotypes are geneti...

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Section: Discussionmentioning

confidence: 92%

Molecular analysis of two mouse dilute locus deletion mutations: spontaneous dilute lethal20J and radiation-induced dilute prenatal lethal Aa2 alleles.

et al. 1990

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“…Six different mutations at the ADA locus have previously been precisely defined in children with ADA deficiency and SCID (13, [24][25][26][27]. We now report the first definition of a mutation that results in partial ADA deficiency in two unrelated children, both of whom express a heat-labile mutant ADA either alone or in combination with a second mutant ADA.…”

Section: Discussionmentioning

confidence: 94%

“…According to the predicted secondary structure, the two different mutations occur at either side of a seven-amino acid stretch with a beta configuration. Both represent loss of hydrophobic amino acids, but in the case of the mutation resulting in total deficiency of ADA and SCID the replacement is by a very polar basic amino acid that is predicted to result in a major increase in hydrophylicity (26)(27)(28), extending back into the beta structure and altering the site of transition to a turn. We have previously reported that there is an apparent increased prevalence of partial ADA deficiency in the Caribbean (2) that did not appear to reflect the spread ofa single mutation due to "founder effect" combined with a high coefficient of inbreeding.…”

Section: Discussionmentioning

confidence: 99%

Identification of a point mutation resulting in a heat-labile adenosine deaminase (ADA) in two unrelated children with partial ADA deficiency.

Hirschhorn¹,

Tzall²,

Ellenbogen³

et al. 1989

J. Clin. Invest.

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We have determined the mutation in a child with partial adenosine deaminase (ADA) deficiency who is phenotypically homozygous for a mutant ADA gene encoding a heat-labile enzyme (Am. J. Hum. . Sequencing of cDNA demonstrated a C to A transversion that results in the replacement of a proline by a glutamine residue at codon 297. As this mutation generated a new recognition site in exon 10 of genomic DNA for the enzyme Alu I, Southern blot analysis was used to establish that this child was indeed homozygous for the mutation. The abnormal restriction fragment generated by this mutation was also found in a second partially ADA-deficient patient who phenotypically is a genetic compound and also expresses a heat-labile ADA (in addition to a more acidic than normal ADA) (Am. J. Hum. Genet. 38:13-25). Sequencing of cDNA clones from the second patient established the identical codon 297 mutation. Transfection of the mutant cDNA into heterologous cells resulted in expression of a heat-labile ADA of normal electrophoretic mobility and isoelectric point, properties exhibited by the ADA in the patients' cells.

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“…1% of normal activity in blood mononuclear cells and B cell lines (complete deficiency) (6,9,10,13), the latter has 4-70% of normal activity (partial deficiency). Structural gene mutations, which presumably diminish enzyme stability or catalytic activity to different extents, occur in both groups (14)(15)(16)(17)(18)(19)(20)(21). The degree of ADA deficiency determines the severity of toxic effects of deoxyadenosine, including dATP pool expansion and inactivation of S-adenosylhomocysteine hydrolase.…”

Section: Introductionmentioning

confidence: 99%

Paradoxical expression of adenosine deaminase in T cells cultured from a patient with adenosine deaminase deficiency and combine immunodeficiency.

Arredondo-Vega¹,

Kurtzberg²,

Chaffee³

et al. 1990

J. Clin. Invest.

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Severe combined immune deficiency due to a homozygous 3.2-kb deletion spanning the promoter and first exon of the adenosine deaminase gene

Cited by 32 publications

References 27 publications

Molecular analysis of two mouse dilute locus deletion mutations: spontaneous dilute lethal20J and radiation-induced dilute prenatal lethal Aa2 alleles.

Molecular analysis of two mouse dilute locus deletion mutations: spontaneous dilute lethal20J and radiation-induced dilute prenatal lethal Aa2 alleles.

Identification of a point mutation resulting in a heat-labile adenosine deaminase (ADA) in two unrelated children with partial ADA deficiency.

Paradoxical expression of adenosine deaminase in T cells cultured from a patient with adenosine deaminase deficiency and combine immunodeficiency.

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