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Other entities represented in this entry:
HGNC Approved Gene Symbol: SORD
Cytogenetic location: 15q21.1 Genomic coordinates (GRCh38): 15:45,023,195-45,077,185 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 15q21.1 | Neuronopathy, distal hereditary motor, autosomal recessive 8 | 618912 | Autosomal recessive | 3 |
Sorbitol dehydrogenase (SORD; EC 1.1.1.14) catalyzes the interconversion of polyols and their corresponding ketoses. The first reaction of the pathway (also called the polyol pathway) is the reduction of glucose to sorbitol by ALDR1 (103880) with NADPH as the cofactor. SORD then oxidizes the sorbitol to fructose using NAD(+) cofactor (summary by Carr and Markham, 1995).
Lee et al. (1994) cloned and sequenced cDNA for human SORD. They found that it translates into a peptide of 356 amino acid residues, 1 more than the sequence previously reported from peptide analysis.
Iwata et al. (1995) cloned a human SORD cDNA as well as the gene. The promoter was shown to contain a CACCC box and 3 putative binding sites for the transcription factor Sp1 (SP1; 189906). Two alternative transcription initiation sites were identified. Northern blots demonstrated expression in most tissues and at particularly high levels in the kidney and lens of the eye.
Carr and Markham (1995) noted that the polyol pathway is particularly active in hyperglycemic states. Although SORD is closely related to the class I long-chain alcohol dehydrogenases, it differs in substrate specificity, catalyzing polyols such as sorbitol and xylitol but having no activity towards primary alcohols.
Iwata et al. (1995) determined that the SORD gene is divided into 9 exons spanning approximately 30 kb.
Carr and Markham (1995) defined the intron/exon boundaries of the SORD gene and identified a number of polymorphic variants.
Donald et al. (1980) assigned the sorbitol dehydrogenase gene to chromosome 15pter-q21 by somatic cell hybridization. By fluorescence in situ hybridization (FISH), Lee et al. (1994) mapped the SORD gene to a single site on 15q15, indicating that it is a single-copy gene. The localization was confirmed by Southern blot hybridization in somatic cell hybrids. Carr and Markham (1995) mapped the SORD gene to chromosome 15 by screening somatic cell hybrid mapping panels by PCR and regionalized it to 15q15 by FISH.
Iwata et al. (1995) mapped the SORD gene by FISH to 15q21.1.
SORD2
Carr et al. (1998) established that 2 very closely homologous SORD sequences lie within 0.5 Mb on chromosome 15. The SORD2 and SORD1 genes are oriented head-to-head in the order cen--SORD2--SORD1--tel. Thus the 2 genes appear to represent an inverted repeat with their 5-prime ends closest together. By fluorescence in situ hybridization, Carr et al. (1998) showed that both genes are located at 15q15.3.
SORD2
The duplicated human sequences SORD1 and SORD2 translate into proteins that differ by only 6 amino acid substitutions in their 335 residues, with a single-nucleotide deletion in exon 7 of SORD2, the apparent loss of exon 1 from SORD2, and an Alu insertion in intron 8 of SORD2 (Carr et al., 1997). To establish when the human SORD duplication occurred, Carr et al. (1998) sequenced the open reading frame of marmoset liver SORD. SORD appeared to be a single gene in this New World monkey. They found that marmoset SORD showed significantly less homology with either SORD1 or SORD2 than the 2 do with each other, suggesting that the human homologs represent a recent gene duplication event. Carr et al. (1998) presented a hypothesis to explain the retention of the redundant SORD2 sequence in the human genome. All evidence seems to point to the conclusion that SORD2 is not transcribed, i.e., is nonfunctional (Carr, 1999).
Autosomal Recessive Distal Hereditary Motor Neuronopathy 8
In 45 affected individuals from 38 unrelated families with autosomal recessive distal hereditary motor neuronopathy-8 (HMNR8; 618912), also known as SORD deficiency with peripheral neuropathy (SORDD), Cortese et al. (2020) identified homozygous or compound heterozygous mutations in the SORD gene (see, e.g., 182500.0001 and 182500.0002). The most common variant was a 1-bp deletion (c.757delG; 182500.0001) in exon 7 of the SORD gene, predicted to result in a frameshift and premature termination (Ala253GlnfsTer27) in the tetramer interface of the protein. The patients were ascertained from 3 large cohorts totaling about 1,000 individuals with peripheral neuropathy who underwent whole-exome or whole-genome sequencing. Segregation of the variants was confirmed in only a few families in which the affected offspring inherited the variants from heterozygous unaffected parents, and only a few families had more than 1 affected individual. Cortese et al. (2020) noted that SORD has a nonfunctional highly homologous paralog, the pseudogene SORD2 or SORD2P: the c.757delG variant is present in SORD2 in over 95% of control chromosomes. Patient-derived fibroblasts showed absence of the SORD protein and a 10-fold increase in intracellular sorbitol compared to controls. Treatment of some patient fibroblasts with aldose reductase inhibitors epalrestat or ranirestat reduced intracellular sorbitol levels. Additional functional studies of the specific variants were not performed. Serum levels of sorbitol were over 100 times higher in 10 patients with the homozygous variant compared to controls. Cortese et al. (2020) noted that the mechanism of axonal damage associated with SORD deficiency is not known, but may include elevated sorbitol levels, oxidative stress, and decreased NADPH.
Liu et al. (2021) screened a cohort of 485 unrelated Chinese patients with hereditary neuropathy by Sanger sequencing, next-generation sequencing, or whole-exome sequencing after PMP22 (601097) duplication was initially excluded. They identified biallelic mutations in the SORD gene in 5 of 78 undiagnosed patients (182500.0001; 182500.0003-182500.0005). Based on this cohort, the authors calculated the frequency of SORDD at 1% in Chinese hereditary neuropathy patients and 6.4% in undiagnosed Chinese hereditary neuropathy patients.
SORD Polymorphism
Op't Hof (1969) stated that 'preliminary studies with human postmortem liver specimens suggest that a polymorphism for SDH isoenzymes exists also in man.' Such was indeed found by Charlesworth (1972). Vaca et al. (1982) described an 'activity polymorphism' of red cell sorbitol dehydrogenase in a Mexican family, ascertained because of bilateral cataracts in 4 of 5 brothers and the father. SORD was assayed because this enzyme converts sorbitol to fructose and sorbitol is implicated in diabetic cataracts. Because of the incomplete correlation of cataracts and SORD deficiency in this family, an etiopathogenic relationship could not be established. Through routine screening, Shin et al. (1984) found SORD deficiency in a family with congenital cataracts. The cataract patients in this family showed a residual activity that was 15 to 20% of the values in healthy subjects. The patients with low values were all male in this family as in the family reported by Vaca et al. (1982).
Carr and Markham (1995) stated that the accumulation and toxicity of sorbitol in specific tissues has been implicated in the development of microvascular problems in some diabetic patients. Inappropriate sorbitol accumulation in some patients may be the result of polymorphic variation in the human SORD gene, causing reduced expression levels or enzymatic activity.
Ng et al. (1998) found that Sord-deficient mice lacked Sord in the sciatic nerve and other various tissues. The mice did not display any obvious phenotype, including peripheral neuropathy. Tissues that normally contain Sord, including the sciatic nerve, accumulated more sorbitol, particularly in diabetic mice. The findings suggested that the levels of sorbitol and fructose in the sciatic nerve of mice do not correlate with nerve conduction deficits associated with diabetes.
Cortese et al. (2020) found that homozygous knockdown of the Sord gene in Drosophila resulted in increased sorbitol levels in fly heads compared to controls. Mutant flies showed a loss of photoreceptor terminals in the lamina layer of the visual system associated with the development of vacuole-like structures in the synaptic lamina layer. These vacuolar anomalies were also observed with neuron-specific knockdown of the Sord gene. Both Sord-deficient fly models showed progressively impaired locomotor activity, consistent with age-dependent neuromuscular dysfunction. Treatment of mutant flies with aldose reductase inhibitors normalized intracellular sorbitol levels, rescued the locomotor defects, and restored the age-dependent synaptic defects.
In affected individuals from 30 unrelated families with autosomal recessive distal hereditary motor neuronopathy-8 (HMNR8; 618912), also known as SORD deficiency with peripheral neuropathy (SORDD), Cortese et al. (2020) identified a homozygous 1-bp deletion (c.757delG, NM_003104.6) in exon 7 of the SORD gene, predicted to result in a frameshift and premature termination (Ala253GlnfsTer27) in the tetramer interface of the protein. Segregation of the variant was confirmed in only a few families in which the affected offspring inherited the variants from heterozygous unaffected parents, and only a few families had more than 1 affected individual. The mutation was found by whole-exome or whole-genome sequencing and confirmed by Sanger sequencing. The variant was present in 623 of 142,588 genomes in the gnomAD database (frequency of 0.004). Cortese et al. (2020) noted that SORD has a nonfunctional highly homologous paralog, the pseudogene SORD2 or SORD2P: the c.757delG variant is present in SORD2 in over 95% of control chromosomes. The authors used Sanger sequencing to confirm that the c.757delG mutation identified in their patients occurred in the SORD gene. Fibroblasts derived from 4 patients who were homozygous for the c.757delG variant showed absence of the SORD protein and a 10-fold increase in intracellular sorbitol compared to controls. Treatment of patient fibroblasts with aldose reductase inhibitors reduced intracellular sorbitol levels. Additional functional studies of the specific variants were not performed. Serum levels of sorbitol were over 100 times higher in 10 patients with the homozygous variant compared to controls. Eight additional patients, including 2 sibs (family 14), with a similar phenotype were compound heterozygous for c.757delG and another SORD variant. The other alleles included R299X (182500.0002), R110P, R100X, A153D, V322I, L10F, and an intragenic deletion (c.316_425+165del). Familial segregation of these variants could be demonstrated in only 2 patients (patients 4 and 37); familial segregation could not be conclusively demonstrated in the other patients. Several of these variants were present in the gnomAD database at a low frequency (less than 0.0001). All patients were ascertained from 3 large cohorts totaling about 1,000 individuals with peripheral neuropathy who underwent whole-exome or whole-genome sequencing.
In 2 unrelated Chinese patients (patients 1 and 2) with SORDD, Liu et al. (2021) identified homozygosity for the c.757delG mutation in the SORD gene. The mutation, which was identified by whole-exome sequencing, was identified in the carrier state in both sets of parents. The mutation was present at a frequency of 0.0046 in 650 Han Chinese healthy individuals and at a frequency of 0.002 in the Asian population in the gnomAD database (v3.0); it was not present in the 1000 Genomes Project database. In 3 additional unrelated Chinese patients with SORDD, Liu et al. (2021) identified compound heterozygosity for the c.757delG mutation with another mutation in the SORD gene: a c.776C-T transition, resulting in an ala259-to-val (A259V; 182500.0003) substitution, in patient 3; a c.731C-T transition, resulting in a pro244-to-leu (182500.0004) substitution, in patient 4; and a c.851T-C transition, resulting in a leu284-to-pro (L284P; 182500.0005) substitution, in patient 5. The parents in each case were carriers. The missense variants in patients 3, 4, and 5 occurred at highly conserved residues and had a minor allele frequency of less than 0.00001 in gnomAD (v3.0). All 3 variants were classified as likely pathogenic according to ACMG guidelines.
In a 60-year-old Italian man (patient 40 from family 33) with autosomal recessive distal hereditary motor neuronopathy-8 (HMNR8; 618912), Cortese et al. (2020) identified compound heterozygous mutations in the SORD gene: a c.895C-T transition (c.895C-T, NM_003104.6) in the SORD gene, resulting in an arg299-to-ter (R299X) substitution in the tetramer interface, and c.757delG (182500.0001). The mutations were found by whole-exome or whole-genome sequencing and confirmed by Sanger sequencing; the parents were unaffected, but not available for familial segregation analysis. Patient fibroblasts showed undetectable SORD protein levels and increased intracellular sorbitol accumulation compared to controls.
For discussion of the c.776C-T transition (c.776C-T, NM_003104) in the SORD gene, resulting in an ala259-to-val (A259V) substitution, that was identified in compound heterozygous state in a patient (patient 3) with autosomal recessive distal hereditary motor neuronopathy-8 (HMNR8; 618912) by Liu et al. (2021), see 182500.0001.
For discussion of the c.731C-T transition (c.731C-T, NM_003104) in the SORD gene, resulting in a pro244-to-leu (P244L) substitution, that was identified in compound heterozygous state in a patient (patient 4) with autosomal recessive distal hereditary motor neuronopathy-8 (HMNR8; 618912) by Liu et al. (2021), see 182500.0001.
For discussion of the c.851T-C transition (c.851T-C, NM_003104) in the SORD gene, resulting in a leu284-to-pro (L284P) substitution, that was identified in compound heterozygous state in a patient (patient 5) with autosomal recessive distal hereditary motor neuronopathy-8 (HMNR8; 618912) by Liu et al. (2021), see 182500.0001.
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Carr, I. M. Personal Communication. Leeds, England 3/1/1999.
Charlesworth, D. Starch-gel electrophoresis of four enzymes from human red blood cells: glyceraldehyde-3-phosphate dehydrogenase, fructoaldolase, glyoxalase II and sorbitol dehydrogenase. Ann. Hum. Genet. 35: 477-484, 1972. [PubMed: 5073693] [Full Text: https://doi.org/10.1111/j.1469-1809.1957.tb01873.x]
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Liu, X., He, J., Yilihamu, M., Duan, X., Fan, D. Clinical and genetic features of biallelic mutations in SORD in a series of Chinese patients with Charcot-Marie-Tooth and distal hereditary motor neuropathy. Front. Neurol. 12: 733926, 2021. [PubMed: 34819907] [Full Text: https://doi.org/10.3389/fneur.2021.733926]
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