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ALDEHYDE DEHYDROGENASE 6 FAMILY, MEMBER A1; ALDH6A1

ALDEHYDE DEHYDROGENASE 6 FAMILY, MEMBER A1; ALDH6A1

Alternative titles; symbolsMETHYLMALONATE SEMIALDEHYDE DEHYDROGENASE; MMSDHHGNC Approved Gene Symbol: ALDH6A1Cytogenetic location: 14q24.3 Genomic coordinate...

Alternative titles; symbols

  • METHYLMALONATE SEMIALDEHYDE DEHYDROGENASE; MMSDH

HGNC Approved Gene Symbol: ALDH6A1

Cytogenetic location: 14q24.3 Genomic coordinates (GRCh38): 14:74,056,846-74,084,452 (from NCBI)

▼ Description
The ALDH6A1 gene encodes methylmalonate semialdehyde dehydrogenase (MMSDH; EC 1.2.1.27), an enzyme that catalyzes the irreversible oxidative decarboxylation of malonate and methylmalonate semialdehydes to acetyl- and propionyl-CoA, respectively. This activity is part of the valine and pyrimidine catabolic pathways. MMSDH is the only aldehyde dehydrogenase known to require CoA (summary by Kedishvili et al., 1992).

▼ Cloning and Expression
Kedishvili et al. (1992) used MMSDH protein sequence information to screen rat and human liver cDNA libraries. The full-length rat cDNA encodes a 535-amino acid polypeptide, of which the first 32 residues are a mitochondrial entry sequence. The polypeptide sequence encoded by the partial human cDNA is 97.7% identical to the rat protein sequence. Northern blot analysis revealed expression in several rat tissues, with highest levels in kidney and liver.

Chambliss et al. (2000) isolated a cDNA encoding the full-length MMSDH transcript from a human liver cDNA library. They identified a leader sequence of 33 amino acids and determined that the mature MMSDH protein contains 502 amino acids, with an estimated molecular mass of 54,386 Da. The full-length MMSDH protein is 97% identical to the rat MMSDH protein.

▼ Gene Structure
By genomic sequence analysis, Chambliss et al. (2000) found that the MMSDH gene contains 12 exons.

▼ Mapping
By electronic PCR, Chambliss et al. (2000) mapped the MMSDH gene to 14q24.3, between markers D14S71 and D14S986.

▼ Molecular Genetics
In a patient with methylmalonate semialdehyde dehydrogenase deficiency (MMSDHD; 614105) reported by Pollitt et al. (1985) and Gray et al. (1987), Chambliss et al. (2000) identified a homozygous mutation in the MMSDH gene (603178.0001).

In 2 unrelated patients with MMSDHD, Sass et al. (2012) identified homozygous mutations in the ALDH6A1 gene (S262Y, 603178.0002 and P62S, 603178.0003). Functional studies of the variants were not performed.

In a patient with MMSDHD, Marcadier et al. (2013) identified compound heterozygous missense mutations in the ALDH6A1 gene (Y172H, 603178.0004 and R535C, 603178.0005). The mutations, which were found by whole-exome sequencing, segregated with the disorder in the family. Patient fibroblasts showed reduced ALDH6A1 activity compared to controls, but direct functional studies of the variants were not performed.

By sequencing the ALDH6A1 gene in a patient with MMSDHD, Dobrowolski et al. (2020) identified a homozygous missense mutation in the ALDH6A1 gene (P421S; 603178.0006). Patient fibroblasts showed reduced MMSDH protein expression compared to controls.

▼ ALLELIC VARIANTS ( 6 Selected Examples):

.0001 METHYLMALONATE SEMIALDEHYDE DEHYDROGENASE DEFICIENCY
ALDH6A1, GLY446ARG (rs72552258)
In a patient with methylmalonate semialdehyde dehydrogenase deficiency (MMSDHD; 614105) previously described by Pollitt et al. (1985) and Gray et al. (1987), Chambliss et al. (2000) identified a homozygous 1336G-A transition in the MMSDH gene, resulting in a gly446-to-arg (G446R) substitution. The mother was heterozygous for the mutation, but the father was unavailable for testing. The patient was likely the product of a consanguineous union. Chambliss et al. (2000) noted that gly446 is conserved in MMSDH between human, rat, bovine, and bacteria.

.0002 METHYLMALONATE SEMIALDEHYDE DEHYDROGENASE DEFICIENCY
ALDH6A1, SER262TYR
In a child, born of consanguineous parents of European ancestry, with methylmalonate semialdehyde dehydrogenase deficiency (MMSDHD; 614105), Sass et al. (2012) identified a homozygous c.785C-A transversion in exon 7 of the ALDH6A1 gene, resulting in a ser262-to-tyr (S262Y) substitution at a highly conserved residue. The unaffected mother was heterozygous for the mutation, which was not found in 210 control chromosomes; paternal DNA was not available. Functional studies of the variant were not performed.

.0003 METHYLMALONATE SEMIALDEHYDE DEHYDROGENASE DEFICIENCY
ALDH6A1, PRO62SER
In a child, born of consanguineous Pakistani parents, with methylmalonate semialdehyde dehydrogenase deficiency (MMSDHD; 614105), Sass et al. (2012) identified a homozygous c.184C-T transition in exon 3 of the ALDH6A1 gene, resulting in a pro62-to-ser (P62S) substitution at a highly conserved residue. Parental DNA was not available for segregation analysis. The mutation was not identified in 160 Pakistani controls, but it was found in 1 of 210 control chromosomes of European descent. Functional studies of the variant were not performed. The patient was originally reported by Shield et al. (2001).

.0004 METHYLMALONATE SEMIALDEHYDE DEHYDROGENASE DEFICIENCY
ALDH6A1, TYR172HIS
In a 3-year-old girl with methylmalonate semialdehyde dehydrogenase deficiency (MMSDHD; 614105), Marcadier et al. (2013) identified compound heterozygous mutations in the ALDH6A1 gene: a c.514T-C transition (c.514T-C, NM_005589) in exon 6, resulting in a tyr172-to-his (Y172H) substitution, and a c.1603C-T transition in exon 12, resulting in an arg535-to-cys (R535C; 603178.0005) substitution. The mutations, which were found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. Both mutations affected highly conserved residues. Neither mutation was found in the 1000 Genomes Project database or in 540 in-house control exomes. The Y172H mutation was not found in the Exome Variant Server database, whereas the R535C mutation was found once in heterozygous state in the Exome Variant Server database. Patient fibroblasts showed reduced ALDH6A1 activity compared to controls, but direct functional studies of the variants were not performed.

.0005 METHYLMALONATE SEMIALDEHYDE DEHYDROGENASE DEFICIENCY
ALDH6A1, ARG535CYS
For discussion of the c.1603C-T transition (c.1603C-T, NM_005589) in the ALDH6A1 gene, resulting in an arg535-to-cys (R535C) substitution, that was found in compound heterozygous state in a girl with methylmalonate semialdehyde dehydrogenase deficiency (MMSDHD; 614105) by Marcadier et al. (2013), see 603178.0004.

.0006 METHYLMALONATE SEMIALDEHYDE DEHYDROGENASE DEFICIENCY
ALDH6A1, PRO421SER
By sequencing the ALDH6A1 gene in a female infant, born to nonconsanguineous East African parents, with methylmalonate semialdehyde dehydrogenase deficiency (MMSDHD; 614105), Dobrowolski et al. (2020) identified a homozygous c.1261C-T transition, resulting in a pro421-to-ser (P421S) substitution. Patient fibroblasts showed nearly absent MMSDH protein expression.

Tags: 14q24.3