One adenosine deaminase allele in a patient with severe combined immunodeficiency contains a point mutation abolishing enzyme activity.

Valerio, D.; Dekker, B.M.M.; Duyvesteyn, M. G. C.; Voorn, L. Van Der; Berkvens, Th.M.; Ormondt, H. van; Eb, A. J. Van Der

doi:10.1002/j.1460-2075.1986.tb04184.x

Cited by 46 publications

(20 citation statements)

References 22 publications

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“…These in turn cause a significant change in the hydropathy profile (Fig. 5) that probably leads to decreased stability of the partially processed SAP-1, as has been shown for more subtle amino acid changes (27,28 6. Nucleotide and amino acid sequences (standard one-letter code) showing complete homology on either side of the insertion site between rat sulfated glycoprotein 1 (SGP-1), normal human, normal human plus 9, and patient plus 33.…”

Section: Resultsmentioning

confidence: 89%

Insertion in the mRNA of a metachromatic leukodystrophy patient with sphingolipid activator protein-1 deficiency.

Zhang

Rafi

Degala

et al. 1990

Proc. Natl. Acad. Sci. U.S.A.

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The lysosomal catabolism of sulfatide requires arylsulfatase A and a specific sphingolipid activator protein, SAP-1. While most patients with metachromatic leukodystrophy have mutations in the gene for arylsulfatase A, some patients have deficient SAP-1, as determined by immunological techniques. We now describe the molecular findings in a patient who died at 22 years of age with SAP-1 deficiency. The DNA polymerase chain reaction was used to amplify regions of cDNA which were subcloned in M13 phage DNA and sequenced by the dideoxy chain-termination method. The patient was found to have a 33-base-pair insertion between nucleotides 777 and -778 (numbered from the A of the ATG initiation codon). No other changes were found in the coding sequence of the cDNA from this patient. At the site of the insertion some normal people have an additional 9 base pairs, which correspond to the last 9 nucleotides at the 3' end of the insertion. The cDNAs from the second-cousin parents were amplified and sequenced, and in both two alleles were identified, one with the 33-base-pair insertion and one with no insertion. Two brothers were found to have only the normal alleles and a sister was found to have the 33-base-pair insertion and a normal allele. The findings confirm studies performed on leukocyte extracts demonstrating normal antigen levels in the two brothers and a lower level in the sister. The presence of i1 additional amino acids in the coding region of mature SAP-1 in this patient causes significant changes in the hydropathy profile compatible with the previous findings at the protein level.The catabolism of most sphingolipids requires both a specific lysosomal enzyme and a specific, relatively low molecular weight protein we call sphingolipid activator protein (SAP) (1). While at least six SAPs have been identified, the exact number is not known. However, it is now obvious that, while most lysosomal disorders are due to defects in lysosomal enzymes, some very serious and fatal disorders are due to defects in SAP (2-5). These include the AB variant of GM2 gangliosidosis, a variant form of metachromatic leukodystrophy, and a variant form of Gaucher disease. While the patients have clear evidence for decreased catabolism of a specific lipid, the lysosomal enzyme activity measured in vitro is normal and there is evidence for decreased levels of a specific SAP in all cases thus far identified (2,5,6).The cDNA coding for the SAP-1 precursor species, called prosaposin by Morimoto et al. (7), has been cloned and sequenced (8,9). Most recently Nakano et al. (10) published the complete corrected sequence, which is in agreement with our unpublished data, except those authors found a 9-base-pair (bp) insertion between nucleotides 777 and 778 (counting from the A of the ATG initiation codon) in clones from normal people. The SAP-1 precursor protein contains four domains of about 80 amino acids, each with similar structural features, including glycosylation sites and proline and cysteine residues (11-13). The domains are prot...

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Section: Resultsmentioning

confidence: 89%

Insertion in the mRNA of a metachromatic leukodystrophy patient with sphingolipid activator protein-1 deficiency.

Zhang

Rafi

Degala

et al. 1990

Proc. Natl. Acad. Sci. U.S.A.

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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: 93%

“…The substitution occurs at a boundary between a turn and a beta configuration in the predicted secondary structure (6) and predicts a modest increase in hydrophylicity extending from a transition of a turn to a beta configuration and into the hydrophobic region ofthe beta configuration (Table II; [28][29][30], consistent with the increased lability to heat observed for this mutant enzyme (2). The mutation occurs seven codons preceeding a mutation in the same exon 10 detected in a patient with ADA-SCID (25). This latter mutation results in replacement of a hydrophobic leucine by the basic amino acid arginine at codon 304.…”

Section: Discussionmentioning

confidence: 96%

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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“…The missense mutations have all been described previously [22][23][24] and all except one have been tested for residual ADA activity in Escherichia coli. 22 For the homozygous missense mutation found in patient U457 with delayed onset of disease, some residual ADA activity would be predicted (class II according to Arredondo-Vega et al 22 ).…”

Section: Ada Molecular Analysismentioning

confidence: 99%

Patients with adenosine deaminase deficiency surviving after hematopoietic stem cell transplantation are at high risk of CNS complications

Hönig

Albert

Schulz

et al. 2006

Blood

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Adenosine deaminase (ADA) deficiency is a systemic metabolic disease that causes an autosomal recessive variant of severe combined immunodeficiency (SCID) and less consistently other complications including neurologic abnormalities. Hematopoietic stem cell transplantation (HSCT) is able to correct the immunodeficiency, whereas control of nonimmunologic complications has not been extensively explored. We applied HSCT in 15 ADA-deficient patients consecutively treated at our institutions since 1982 and analyzed long-term outcome.

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One adenosine deaminase allele in a patient with severe combined immunodeficiency contains a point mutation abolishing enzyme activity.

Cited by 46 publications

References 22 publications

Insertion in the mRNA of a metachromatic leukodystrophy patient with sphingolipid activator protein-1 deficiency.

Insertion in the mRNA of a metachromatic leukodystrophy patient with sphingolipid activator protein-1 deficiency.

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

Patients with adenosine deaminase deficiency surviving after hematopoietic stem cell transplantation are at high risk of CNS complications

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