Molecular Pathogenesis
The mechanism of pathogenesis of the GALT D2 allele was a point of some confusion in the past (reviewed in Carney et al [2009]), likely reflecting the complex nature of the allele and the fact that the linked 4-bp promoter deletion (c.-119_-116delGTCA) was not initially recognized. The consensus is now that this 4-bp promoter deletion is actually the causal variant, leading to slight impairment of expression of what is a fully functional GALT protein.
The mechanism of pathogenesis of different GALT pathogenic variants as a cause of classic / clinical variant galactosemia is described in Classic Galactosemia and Clinical Variant Galactosemia.
Gene structure. See Classic Galactosemia and Clinical Variant Galactosemia for information about GALT. See also Table A, Gene.
Benign variants
Duarte variant (D2) allele. Some consider the D
2 variant allele itself to be benign. Five sequence changes in
cis configuration are found on the D
2 allele.
Los Angeles (or D1) variant allele results in no diminution of GALT enzyme activity and is considered benign. Note: The Los Angeles (LA)
GALT variant (D
1) has the identical c.940A>G
missense variant as the D
2 variant but does not have the c.-119_-116delGTCA promoter
deletion. Instead, it is in
cis configuration with the silent variant c.652C>T (p.Leu218=, also called L218L). See
Classic Galactosemia and Clinical Variant Galactosemia. The D
1 variant allele does not cause galactosemia and is associated with normal or slightly increased erythrocyte GALT enzyme activity (reviewed in
Carney et al [2009]).
Table 3.
GALT Variants Associated with the D2 Allele Discussed in This GeneReview
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DNA Nucleotide Change (Alias 1) | Predicted Protein Change | Reference Sequences |
---|
c.-119_-116delGTCA | NA 2 |
NM_000155.2
NP_000146.2
|
c.940A>G | p.Asn314Asp |
c.378-27G>C (IVS4-27G>C) | NA |
c.508-24G>A (IVS5-24G>A) | NA |
c.507+62G>A (IVS5-62G>A) | NA |
Variants listed in the table have been provided by the authors. GeneReviews staff have not independently verified the classification of variants.
GeneReviews follows the standard naming conventions of the Human Genome Variation Society (varnomen.hgvs.org). See Quick Reference for an explanation of nomenclature.
- 1.
Variant designation that does not conform to current naming conventions
- 2.
Interpretation of molecular genetic test results. Although rare, some individuals with Duarte variant galactosemia are homozygous for c.940A>G (p.Asn314Asp, also called N314D) and heterozygous for a pathogenic GALT variant, indicating that the pathogenic variant coexists in these individuals in a cis configuration with either a D2 or D1 allele.
Also, rarely, some individuals with classic galactosemia (who by definition have biallelic GALT pathogenic variants) may also have either a D2 or D1 allele in cis configuration with one or both pathogenic GALT variants.
Therefore, demonstrating the presence of the D2 variant – or any of the individual GALT sequence changes associated with a D2 allele (e.g., c.940A>G; p.Asn314Asp, or N314D) – does not confirm a diagnosis of Duarte variant galactosemia or rule out a diagnosis of classic galactosemia. The presence of GALT variants must always be interpreted in conjunction with GALT enzyme activity levels.
Of note, the parents of a child with an identified D2
GALT variant allele and a GALT pathogenic variant allele can undergo molecular genetic testing themselves to determine whether each parent carries one variant, or whether both GALT variants are found in one parent while the other parent carries neither variant.
If each parent carries one variant found in the child, the D
2 and pathogenic
GALT variants identified in the child are in
trans configuration (on separate chromosomes) consistent with a diagnosis of Duarte variant galactosemia in the child.
If one parent carries both the D
2 and pathogenic
GALT variants identified in the child while the other parent carries neither, the D
2 and pathogenic
GALT variants in the child are most likely in
cis configuration (coexisting on the same
chromosome) consistent with a diagnosis of unaffected galactosemia
carrier rather than Duarte variant galactosemia in the child. In this scenario, the child would also be expected to show a GALT enzyme activity level close to 50% of control.
Pathogenic variants. See Classic Galactosemia and Clinical Variant Galactosemia for information on other GALT alleles.
Normal gene product. The normal human GALT protein contains 379 amino acids and functions as a homodimer with two active sites [Wedekind et al 1995, Holden et al 2003].
A GALT allele with only the c.940A>G (p.Asn314Asp) variant is thought to produce a fully functional protein (reviewed in Carney et al [2009]).
Abnormal gene product. Abnormal gene products associated with different pathogenic alleles of GALT are described in Classic Galactosemia and Clinical Variant Galactosemia.