ALAD K59N - GET-Evidence

Note: This variant has not been sufficiently evaluated by a GET-Evidence editor.

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Curation:
Currentness:

ALAD K59N

(ALAD Lys59Asn)


Short summary

This variant was implicated in causing increased susceptibility to lead poisoning, but evidence was not very significant and later reports have conflicting evidence (may even support a weakly protective effect in a few cases).

Variant evidence
Computational 2

Protein binds lead, change from positive to neutral charged amino acid is predicted to increase lead binding efficiency

See Wetmur JG et al. 1991 (1716854).

Functional

No functional data

Case/Control

Studies have conflicting evidence regarding how this variant affects blood lead levels and the effect on cognition.

See Astrin KH et al. 1987 (3442386), Ziemsen B et al. 1986 (3770964), Krieg EF Jr et al. 2009 (19686844).

Familial

No familial evidence

 
Clinical importance
Severity 1

Increased susceptibility to lead poisoning, unlikely to have symptoms

Treatability 3

Treatable by decreasing exposure to lead

Penetrance -
 

Impact

Insufficiently evaluated pathogenic

(The "insufficiently evaluated" qualifier is assigned automatically based on the above evidence and importance scores.)

Inheritance pattern

undefined

Summary of published research, and additional commentary

 

Allele frequency

  • G @ chr9:116153891: 5.9% (637/10758) in EVS
  • Frequency shown in summary reports: 5.9% (637/10758)

Publications
 

Wetmur JG, Kaya AH, Plewinska M, Desnick RJ. Molecular characterization of the human delta-aminolevulinate dehydratase 2 (ALAD2) allele: implications for molecular screening of individuals for genetic susceptibility to lead poisoning. Am J Hum Genet. 1991 Oct;49(4):757-63. PubMed PMID: 1716854; PubMed Central PMCID: PMC1683158.

Connects the ALAD2 allele with this genetic change. Mentions Ziemsen et al. 1986 & Astrin et al. 1987, saying “data from these two
independent studies indicated that individuals with the ALAD 1-2 or ALAD 2-2 isozyme phenotype had significantly higher levels of blood lead than did similarly exposed individuals who were homozygous for ALAD1 allele”.

Astrin KH, Bishop DF, Wetmur JG, Kaul B, Davidow B, Desnick RJ. delta-Aminolevulinic acid dehydratase isozymes and lead toxicity. Ann N Y Acad Sci. 1987;514:23-9. PubMed PMID: 3442386.

Samples were collected from “individuals who had high free erythrocytic protoporphyrin (FEP) levels that could be attributable to lead intoxication” and tested for genotype & blood lead level, the latter was split into < 30 ug/dl and >=30. Treating that divide as “case/control”, the total numbers are: Case: 1-1: 136, 1-2: 95, 2-2: 36. Control: 1-1: 915, 1-2: 841, 2-2: 102. Counting alleles, this is: case+: 167, case-: 367, control+: 1045, control-: 2671. Although the authors claim their data supports increased lead susceptibility, they do not report a significance score and according to Fisher’s Exact Test the data is not statistically significant. (OR = 1.16, p = 0.137)

Ziemsen B, Angerer J, Lehnert G, Benkmann HG, Goedde HW. Polymorphism of delta-aminolevulinic acid dehydratase in lead-exposed workers. Int Arch Occup Environ Health. 1986;58(3):245-7. PubMed PMID: 3770964.

Measures blood lead levels of lead-exposed workers, split along genotype (ug/100ml): 1-1 homozygous: 38 (17 std. dev., n = 160), 2-1 heterozygous: 44 (17 std. dev., n = 32), 2-2 homozygous: 56 (18 std. dev., n = 10).

Krieg EF Jr, Butler MA, Chang MH, Liu T, Yesupriya A, Lindegren ML, Dowling N; CDC/NCI NHANES III Genomics Working Group. Lead and cognitive function in ALAD genotypes in the third National Health and Nutrition Examination Survey. Neurotoxicol Teratol. 2009 Nov-Dec;31(6):364-71. Epub 2009 Aug 15. PubMed PMID: 19686844.

Notes contradicting results, “in adults with lower concentrations, the opposite has been found” (i.e. lower blood lead in ALAD2 genotype). They look at cognitive function and blood lead levels and found few significant correlations. Of those they call significant, they report that reaction time improved as blood lead concentration increased in individuals carrying one or two copies of ALAD2, and that the mean blood lead concentration of children with one or two copies of ALAD2 was lower than children without. In all, this is contradicting evidence for ALAD2 causing increased susceptibility to lead; it may even have a mildly protective effect.

Genomes
 

hu011C57 - CGI sample GS01669-DNA_B05 from PGP sample 86486261
het G @ chr9:116153891

 

hu034DB1 - CGI sample GS00253-DNA_A02_200_37
het G @ chr9:116153891

 

hu4CA5B9 - CGI sample GS01669-DNA_B03 from PGP sample 14427241
hom G @ chr9:116153891

 

hu72A81D - CGI sample GS01173-DNA_C02 from PGP sample 10366372
het G @ chr9:116153891

 

hu8229AE - CGI sample GS01173-DNA_A07 from PGP sample 96240009
het G @ chr9:116153891

 

huBAAC98 - CGI sample GS01173-DNA_F02 from PGP sample 70008981
het G @ chr9:116153891

 

huD81F3D - CGI sample GS01173-DNA_D06 from PGP sample 69488604
het G @ chr9:116153891

 

Other external references
 

    dbSNP
  • rs1800435
    www.ncbi.nlm.nih.gov/projects/SNP/snp_ref.cgi
    PolyPhen-2
  • Score: 0 (benign)

Other in silico analyses
 

  • NBLOSUM100 score = 1
  • GET-Evidence autoscore = 3

Edit history
 

Gene search

"GENE" or "GENE A123C":

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