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Origins, distribution and expression of the Duarte-2 (D2) allele of galactose-1-phosphate uridylyltransferase.
Hum Mol Genet. 2009 May 01; 18(9):1624-32.HM

Abstract

Duarte galactosemia is a mild to asymptomatic condition that results from partial impairment of galactose-1-phosphate uridylyltransferase (GALT). Patients with Duarte galactosemia demonstrate reduced GALT activity and carry one profoundly impaired GALT allele (G) along with a second, partially impaired GALT allele (Duarte-2, D2). Molecular studies reveal at least five sequence changes on D2 alleles: a p.N314D missense substitution, three intronic base changes and a 4 bp deletion in the 5' proximal sequence. The four non-coding sequence changes are unique to D2. The p.N314D substitution, however, is not; it is found together with a silent polymorphism, p.L218(TTA), on functionally normal Duarte-1 alleles (D1, also called Los Angeles or LA alleles). The HapMap database reveals that p.N314D is a common human variant, and cross-species comparisons implicate D314 as the ancestral allele. The p.N314D substitution is also functionally neutral in mammalian cell and yeast expression studies. In contrast, the 4 bp 5' deletion characteristic of D2 alleles appears to be functionally impaired in reporter gene transfection studies. Here we present allele-specific qRT-PCR evidence that D2 alleles express less mRNA in vivo than their wild-type counterparts; the difference is small but statistically significant. Furthermore, we characterize the prevalence of the 4 bp deletion in GG, NN and DG populations; the deletion appears exclusive to D2 alleles. Combined, these data strongly implicate the 4 bp 5' deletion as a causal mutation in Duarte galactosemia and suggest that direct tests for this deletion, as proposed here, could enhance or supplant current tests, which define D2 alleles on the basis of the presence and absence of linked coding sequence polymorphisms.

Authors+Show Affiliations

Emory University, Atlanta, USANo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

19224951

Citation

Carney, Amanda E., et al. "Origins, Distribution and Expression of the Duarte-2 (D2) Allele of Galactose-1-phosphate Uridylyltransferase." Human Molecular Genetics, vol. 18, no. 9, 2009, pp. 1624-32.
Carney AE, Sanders RD, Garza KR, et al. Origins, distribution and expression of the Duarte-2 (D2) allele of galactose-1-phosphate uridylyltransferase. Hum Mol Genet. 2009;18(9):1624-32.
Carney, A. E., Sanders, R. D., Garza, K. R., McGaha, L. A., Bean, L. J., Coffee, B. W., Thomas, J. W., Cutler, D. J., Kurtkaya, N. L., & Fridovich-Keil, J. L. (2009). Origins, distribution and expression of the Duarte-2 (D2) allele of galactose-1-phosphate uridylyltransferase. Human Molecular Genetics, 18(9), 1624-32. https://doi.org/10.1093/hmg/ddp080
Carney AE, et al. Origins, Distribution and Expression of the Duarte-2 (D2) Allele of Galactose-1-phosphate Uridylyltransferase. Hum Mol Genet. 2009 May 1;18(9):1624-32. PubMed PMID: 19224951.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Origins, distribution and expression of the Duarte-2 (D2) allele of galactose-1-phosphate uridylyltransferase. AU - Carney,Amanda E, AU - Sanders,Rebecca D, AU - Garza,Kerry R, AU - McGaha,Lee Anne, AU - Bean,Lora J H, AU - Coffee,Bradford W, AU - Thomas,James W, AU - Cutler,David J, AU - Kurtkaya,Natalie L, AU - Fridovich-Keil,Judith L, Y1 - 2009/02/18/ PY - 2009/2/20/entrez PY - 2009/2/20/pubmed PY - 2009/7/15/medline SP - 1624 EP - 32 JF - Human molecular genetics JO - Hum Mol Genet VL - 18 IS - 9 N2 - Duarte galactosemia is a mild to asymptomatic condition that results from partial impairment of galactose-1-phosphate uridylyltransferase (GALT). Patients with Duarte galactosemia demonstrate reduced GALT activity and carry one profoundly impaired GALT allele (G) along with a second, partially impaired GALT allele (Duarte-2, D2). Molecular studies reveal at least five sequence changes on D2 alleles: a p.N314D missense substitution, three intronic base changes and a 4 bp deletion in the 5' proximal sequence. The four non-coding sequence changes are unique to D2. The p.N314D substitution, however, is not; it is found together with a silent polymorphism, p.L218(TTA), on functionally normal Duarte-1 alleles (D1, also called Los Angeles or LA alleles). The HapMap database reveals that p.N314D is a common human variant, and cross-species comparisons implicate D314 as the ancestral allele. The p.N314D substitution is also functionally neutral in mammalian cell and yeast expression studies. In contrast, the 4 bp 5' deletion characteristic of D2 alleles appears to be functionally impaired in reporter gene transfection studies. Here we present allele-specific qRT-PCR evidence that D2 alleles express less mRNA in vivo than their wild-type counterparts; the difference is small but statistically significant. Furthermore, we characterize the prevalence of the 4 bp deletion in GG, NN and DG populations; the deletion appears exclusive to D2 alleles. Combined, these data strongly implicate the 4 bp 5' deletion as a causal mutation in Duarte galactosemia and suggest that direct tests for this deletion, as proposed here, could enhance or supplant current tests, which define D2 alleles on the basis of the presence and absence of linked coding sequence polymorphisms. SN - 1460-2083 UR - https://www.unboundmedicine.com/medline/citation/19224951/Origins_distribution_and_expression_of_the_Duarte_2__D2__allele_of_galactose_1_phosphate_uridylyltransferase_ L2 - https://academic.oup.com/hmg/article-lookup/doi/10.1093/hmg/ddp080 DB - PRIME DP - Unbound Medicine ER -