Molecular Basis of Galactosemia: Mutations and Polymorphisms in the Gene Encoding Human Galactose-1-phosphate Uridylyltransferase

Overview

Journal Proc Natl Acad Sci U S A

Specialty Science

Date 1991 Apr 1

PMID 2011574

Citations 32

Authors

J K Reichardt

S L Woo

Affiliations

Soon will be listed here.

Abstract

We describe the molecular characterization of two mutations responsible for galactosemia, an inherited disorder of galatose metabolism that causes jaundice, cataracts, and mental retardation in humans. The coding region of galactose-1-phosphate uridylyltransferase (GALT; UDPglucose:alpha-D-galactose-1-phosphate uridylyltransferase, EC 2.7.7.12) was amplified by the polymerase chain reaction from total cDNA of a classic galactosemic individual and was characterized by direct sequencing of the products. Two missense mutations were identified: (i) replacement of valine-44 by methionine and (ii) replacement of methionine-142 by lysine. These mutations led to a drastic reduction in GALT activity when individual mutant cDNAs were overexpressed in a mammalian cell system, although full-length protein is synthesized in this assay. The two galactosemia mutations account for 3 of the 15 galactosemia alleles analyzed. These results suggest that galactosemia is caused by a variety of mutations, which might be responsible for the observed clinical heterogeneity of this disorder. We also present the molecular characterization of two GALT polymorphisms: (i) replacement of leucine-62 by methionine and (ii) replacement of asparagine-314 by aspartate. It appears that galactosemia mutations tend to occur in regions that are highly conserved throughout evolution while the polymorphisms change variable residues.

Citing Articles

Early postnatal alterations in follicular stress response and survival in a mouse model of Classic Galactosemia.

Hagen-Lillevik S, Johnson J, Lai K J Ovarian Res. 2022; 15(1):122.

PMID: 36414970 PMC: 9682695. DOI: 10.1186/s13048-022-01049-2.

Classic galactosaemia in the Greek Cypriot population: An epidemiological and molecular study.

Papachristoforou R, Petrou P, Sawyer H, Williams M, Drousiotou A Ann Hum Genet. 2019; 83(5):291-298.

PMID: 30994193 PMC: 6766971. DOI: 10.1111/ahg.12318.

Alterations of Gut Microbiota in Cholestatic Infants and Their Correlation With Hepatic Function.

Guo C, Li Y, Wang P, Li Y, Qiu C, Li M Front Microbiol. 2018; 9:2682.

PMID: 30483228 PMC: 6243132. DOI: 10.3389/fmicb.2018.02682.

Sweet and sour: an update on classic galactosemia.

Coelho A, Rubio-Gozalbo M, Vicente J, Rivera I J Inherit Metab Dis. 2017; 40(3):325-342.

PMID: 28281081 PMC: 5391384. DOI: 10.1007/s10545-017-0029-3.

Clinical profile and molecular characterization of Galactosemia in Brazil: identification of seven novel mutations.

Garcia D, Camelo Jr J, Molfetta G, Turcato M, Souza C, Porta G BMC Med Genet. 2016; 17(1):39.

PMID: 27176039 PMC: 4866286. DOI: 10.1186/s12881-016-0300-8.

References

Sly W, Sekhon G, Kennett R, Bodmer W, Bodmer J . Permanent lymphoid lines from genetically marked lymphocytes: success with lymphocytes recovered from frozen storage. Tissue Antigens. 1976; 7(3):165-72. DOI: 10.1111/j.1399-0039.1976.tb01047.x. View

Flach J, Reichardt J, Elsas 2nd L . Sequence of a cDNA encoding human galactose-1-phosphate uridyl transferase. Mol Biol Med. 1990; 7(4):365-9. View

Levy H, Hammersen G . Newborn screening for galactosemia and other galactose metabolic defects. J Pediatr. 1978; 92(6):871-7. DOI: 10.1016/s0022-3476(78)80351-5. View

Chirgwin J, Przybyla A, MacDonald R, Rutter W . Isolation of biologically active ribonucleic acid from sources enriched in ribonuclease. Biochemistry. 1979; 18(24):5294-9. DOI: 10.1021/bi00591a005. View

GITZELMANN R, Steinmann B . Galactosemia: how does long-term treatment change the outcome?. Enzyme. 1984; 32(1):37-46. DOI: 10.1159/000469448. View

Orkin S, Kazazian Jr H . The mutation and polymorphism of the human beta-globin gene and its surrounding DNA. Annu Rev Genet. 1984; 18:131-71. DOI: 10.1146/annurev.ge.18.120184.001023. View

Lemaire H, Muller-Hill B . Nucleotide sequences of the gal E gene and the gal T gene of E. coli. Nucleic Acids Res. 1986; 14(19):7705-11. PMC: 311790. DOI: 10.1093/nar/14.19.7705. View

Cooper D, Youssoufian H . The CpG dinucleotide and human genetic disease. Hum Genet. 1988; 78(2):151-5. DOI: 10.1007/BF00278187. View

Jacobs K, Rudersdorf R, Neill S, Dougherty J, Brown E, Fritsch E . The thermal stability of oligonucleotide duplexes is sequence independent in tetraalkylammonium salt solutions: application to identifying recombinant DNA clones. Nucleic Acids Res. 1988; 16(10):4637-50. PMC: 336654. DOI: 10.1093/nar/16.10.4637. View

10.

Reichardt J, Berg P . Cloning and characterization of a cDNA encoding human galactose-1-phosphate uridyl transferase. Mol Biol Med. 1988; 5(2):107-22. View

11.

Webster T, Dickson R . Nucleotide sequence of the galactose gene cluster of Kluyveromyces lactis. Nucleic Acids Res. 1988; 16(16):8192-4. PMC: 338536. DOI: 10.1093/nar/16.16.8192. View

12.

Reichardt J, Berg P . Conservation of short patches of amino acid sequence amongst proteins with a common function but evolutionarily distinct origins: implications for cloning genes and for structure-function analysis. Nucleic Acids Res. 1988; 16(18):9017-26. PMC: 338649. DOI: 10.1093/nar/16.18.9017. View

13.

Piantanida T . The molecular genetics of color vision and color blindness. Trends Genet. 1988; 4(11):319-23. DOI: 10.1016/0168-9525(88)90110-2. View

14.

Worton R, Thompson M . Genetics of Duchenne muscular dystrophy. Annu Rev Genet. 1988; 22:601-29. DOI: 10.1146/annurev.ge.22.120188.003125. View

15.

Woo S . Molecular basis and population genetics of phenylketonuria. Biochemistry. 1989; 28(1):1-7. DOI: 10.1021/bi00427a001. View

16.

Antonarakis S, Kazazian Jr H . The molecular basis of hemophilia A in man. Trends Genet. 1988; 4(8):233-7. DOI: 10.1016/0168-9525(88)90156-4. View

17.

Heitman J, Treisman J, Davis N, Russel M . Cassettes of the f1 intergenic region. Nucleic Acids Res. 1989; 17(11):4413. PMC: 317983. DOI: 10.1093/nar/17.11.4413. View

18.

Stout J, Caskey C . The Lesch-Nyhan syndrome: clinical, molecular and genetic aspects. Trends Genet. 1988; 4(6):175-8. DOI: 10.1016/0168-9525(88)90024-8. View

19.

Riordan J, Rommens J, Kerem B, Alon N, Rozmahel R, Grzelczak Z . Identification of the cystic fibrosis gene: cloning and characterization of complementary DNA. Science. 1989; 245(4922):1066-73. DOI: 10.1126/science.2475911. View

20.

Kerem B, Rommens J, Buchanan J, Markiewicz D, Cox T, Chakravarti A . Identification of the cystic fibrosis gene: genetic analysis. Science. 1989; 245(4922):1073-80. DOI: 10.1126/science.2570460. View