Alternative titles; symbols
HGNC Approved Gene Symbol: SLC22A5
SNOMEDCT: 21764004; ICD10CM: E71.41; ICD9CM: 277.81;
Cytogenetic location: 5q31.1 Genomic coordinates (GRCh38): 5:132,369,710-132,395,612 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 5q31.1 | Carnitine deficiency, systemic primary | 212140 | Autosomal recessive | 3 |
Wu et al. (1998) cloned a full-length cDNA for OCTN2 (SLC22A5), a member of the organic cation transporter family, from a human placental trophoblast cell line. The OCTN2 cDNA encodes a predicted 557-amino acid protein.
Tamai et al. (1998) cloned OCTN2 from a human kidney cDNA library. The deduced protein shares 75.8% similarity with OCTN1 (604190). Northern blot analysis showed that OCTN2 is strongly expressed in kidney, skeletal muscle, heart, and placenta.
Wu et al. (1998) determined that the OCTN2 gene consists of 10 exons and spans approximately 26 kb.
Functional expression studies of OCTN2 in HEK293 cells by Tamai et al. (1998) indicated that OCTN2 is a physiologically important, high affinity carnitine transporter that shows significant sodium ion dependence.
Heintzman et al. (2007) determined the chromatin modification states in high resolution along 30 Mb of the human genome and found that active promoters are marked by trimethylation of lys4 of histone H3 (H3K4), whereas enhancers were marked by monomethylation, but not trimethylation, of H3K4. They developed computational algorithms using these distinct chromatin signatures to identify new regulatory elements, predicting over 200 promoters and 400 enhancers within the 30-Mb region. This approach accurately predicted the location and function of independently identified regulatory elements with high sensitivity and specificity and uncovered a novel functional enhancer for the carnitine transporter SLC22A5 (OCTN2). The results provided insight into the connections between chromatin modifications and transcriptional regulatory activity and provided a new tool for the functional annotation of the human genome.
Primary Systemic Carnitine Deficiency
Based on the observation that OCTN2 has the ability to transport carnitine in a sodium-dependent manner, Nezu et al. (1999) searched for mutations in the gene encoding OCTN2, designated SLC22A5, both in the mouse model ('jvs') of primary systemic carnitine deficiency and in the human disorder (CDSP; 212140). In the mouse model, they found a loss-of-function missense mutation, a substitution of a hydrophilic amino acid (arg) for a hydrophobic residue (leu) in a membrane-spanning region of the OCTN2 transporter. In 3 unrelated families with systemic carnitine deficiency, they found that CDSP patients were carrying mutations in the SLC22A5 gene (603377.0001-603377.0004).
Lamhonwah and Tein (1998) studied the expression of OCTN2 in cultured fibroblasts and lymphoblasts from 2 unrelated patients in whom they had previously documented a carnitine uptake defect (Tein et al., 1990). In both patients, they found truncating mutations in the cDNA (603377.0005-603377.0007).
Wang et al. (1999) identified mutations in the OCTN2 gene in 2 unrelated patients with CDSP, 1 homozygous and the other a compound heterozygous (603377.0008-603377.0009).
Wang et al. (2000) studied 4 European families with primary carnitine deficiency and found homozygosity for novel missense mutations in 3 patients. The fourth patient was compound heterozygous for R169W (603377.0014) and W351R (603377.0015). Further studies failed to indicate a correlation between residual carnitine transport and severity of the phenotype or age at presentation, which varies from early in life with hypoketotic hypoglycemia to later in life with skeletal myopathy or cardiomyopathy.
Wang et al. (2001) reported 4 novel mutations in the SLC22A5 gene causing primary carnitine deficiency. Alleles introducing premature stop codons reduced the levels of the mRNA.
Lamhonwah et al. (2002) performed mutation screening of the OCTN2 gene in 11 individuals with CDSP by direct nucleotide sequencing of PCR products of all 10 exons. Carnitine uptake in cultured skin fibroblasts ranged from 1 to 20% of normal controls. Eleven mutations were described. No correlation between residual uptake and severity of clinical presentation was found, which suggested that the wide phenotypic variability was likely related to exogenous stressors that exacerbated carnitine deficiency.
Rahbeeni et al. (2002) reported 2 novel mutations in the OCTN2 gene from 2 Saudi patients with systemic carnitine deficiency.
Dobrowolski et al. (2005) validated the dye-binding/high-resolution thermal denaturation method for the identification of mutations in the SLC22A5 gene and expanded the mutational spectrum in primary carnitine deficiency.
Amat di San Filippo et al. (2006) found by confocal microscopy that several OCTN2 missense mutants matured normally to the plasma membrane. By contrast, other mutations caused significant retention of the mutant OCTN2 transporter in the cytoplasm. Failed maturation to the plasma membrane is a common mechanism in disorders affecting membrane transporters/ion channels, including cystic fibrosis. To correct this defect, Amat di San Filippo et al. (2006) tested whether drugs reducing the efficiency of protein degradation in the endoplasmic reticulum (phenylbutyrate, curcumin) or capable of binding the OCTN2 carnitine transporter (verapamil, quinidine) could improve carnitine transport. Prolonged incubation with phenylbutyrate, quinidine, and verapamil partially stimulated carnitine transport, while curcumin was ineffective. Thus, pharmacologic therapy can be effective in partially restoring activity of mutant transporters.
El-Hattab et al. (2010) reported 5 families in which low free carnitine levels in the infants' newborn screen led to the diagnosis of maternal systemic primary carnitine deficiency. Affected mothers were compound heterozygotes or homozygotes for missense mutations. All infants were asymptomatic at the time of diagnosis, and 1 was found to have systemic primary carnitine deficiency. Three mothers were asymptomatic, one had decreased stamina during pregnancy, and the fifth had mild fatigability and developed preeclampsia. El-Hattab et al. (2010) concluded that these findings provided further evidence that systemic primary carnitine deficiency presents with a broad clinical spectrum from a metabolic decomposition in infancy to an asymptomatic adult.
Inflammatory Bowel Disease 5
For discussion of an association between variation in the SLC22A5 gene and inflammatory bowel disease-5, see 606348.
Shekhawat et al. (2007) found that Octn2 +/- mice were viable and fertile, but Octn2 -/- mice survived only 4 to 5 weeks without carnitine supplementation. Octn2 -/- mice developed enlarged fatty liver, steatosis of other organs, and hypertrophic cardiomyopathy. In addition, Octn2 -/- mice developed intestinal villous atrophy and intestinal breakdown and inflammation with intense lymphocyte and macrophage infiltration, leading to ulcer formation and gut perforation. Shekhawat et al. (2007) observed increased apoptosis of Octn2 -/- gut epithelial cells and upregulation of Hsf1 (140580) and several heat shock proteins (e.g., HSPA1A; 140550), which regulate OCTN2 gene expression. Intestinal and colonic epithelial cells in wildtype mice showed high expression and activity of enzymes of the beta-oxidation pathway (e.g., ADADM; 607008). Shekhawat et al. (2007) concluded that carnitine-dependent oxidation of long-chain fatty acids in mitochondria is essential for normal gut function.
In 2 affected sibs with systemic carnitine deficiency (CDSP; 212140) in a Japanese family reported by Matsuishi et al. (1985), Nezu et al. (1999) found homozygosity for a 113-bp deletion in the SLC22A5 gene that encompassed the initiation codon in exon 1. The next available ATG in the correct frame was at codon 177, translation initiation at which would lead to loss of 2 transmembrane domains in the protein.
In a patient with primary systemic carnitine deficiency (CDSP; 212140) reported by Shoji et al. (1998), Nezu et al. (1999) found compound heterozygosity for mutations in the SLC22A5 gene. One allele had a frameshift caused by a single cytosine insertion just after the start codon. The second allele had a single base substitution in codon 132 (the first codon of exon 2), which changed a tryptophan (TGG) to a stop codon (TGA) (W132X).
See 603377.0002 and Nezu et al. (1999).
In a Chinese family with systemic primary carnitine deficiency (CDSP; 212140) reported by Tang et al. (1998), Tang et al. (1999) described compound heterozygosity for a truncating mutation (trp132 to ter) and a missense mutation (pro478 to leu; 603377.0011) in the SLC22A5 gene. Expression of mutant cDNAs revealed virtually no uptake activity for both mutations. The proband was the second child in the family. He was admitted with acute metabolic derangement at the age of 6 months, went into cardiac arrest, and succumbed shortly after admission. Peri-mortem serum free carnitine was very low with a normal free carnitine-to-acylcarnitine ratio. The diagnosis was established by measurement of carnitine uptake into fibroblasts, which was only 5% of normal. His elder sister had died after similar presentation. Physiologic studies in the parents indicated that both were heterozygotes for a defective carnitine transporter.
In a 5-year-old boy with systemic carnitine deficiency (CDSP; 212140), Nezu et al. (1999) found that the SLC22A5 gene carried an acceptor splice site mutation, a G-to-A transition in the last nucleotide of intron 8. The most likely consequence of this mutation, the joining of exon 8 with exon 10, was predicted to result in the creation of a premature stop codon after 2 residues. The patient had recurrent episodes of Reye syndrome, including encephalopathy, hyperammonemia, elevated liver enzymes, and liver steatosis, with hypoglycemia between ages 2 and 3 years. He had been taking carnitine orally without any recurrence of the episodes.
In 2 patients with carnitine uptake defect (CDSP; 212140) reported by Tein et al. (1990), Lamhonwah and Tein (1998) found compound heterozygosity for mutations in the SLC22A5 gene. Both patients showed a partial cDNA deletion of nucleotides 255-1649, resulting in a predicted truncated protein of 92 amino acids. In patient 1, the second mutant allele carried a 19-bp insertion between nucleotides 874 and 875, resulting in a frameshift and yielding a predicted truncated protein of 284 amino acids (603377.0006); in patient 2, the second mutant allele had a deletion of nucleotides 875-1046, resulting in a predicted truncated protein of 237 amino acids (603377.0008). Patient 1 was a male of Italian descent; patient 2 was a female of Mexican descent with a family history of an affected brother who had died of cardiomyopathy. Both children had early-onset myopathy, cardiomyopathy, and failure to thrive with less than 5% of control carnitine concentrations in muscle and had a dramatic improvement in growth, strength, and cardiac function following institution of high dose oral carnitine supplementation. Patient 1 had a striking decrease in renal reabsorption of carnitine (52%; normal greater than 95%) despite low serum carnitine concentrations. His muscle carnitine concentration increased to only 13% of control after carnitine supplementation; however, this was sufficient to result in a resolution of the lipid storage and a restoration of motor power.
For discussion of the 19-bp insertion between nucleotides 874 and 875 in the SLC22A5 gene that was found in compound heterozygous state in a patient with carnitine uptake defect (CDSP; 212140) by Lamhonwah and Tein (1998), see 603377.0005.
For discussion of the 171-bp deletion of nucleotides 875-1046 in the SLC22A5 gene that was found in compound heterozygous state in a patient with carnitine uptake defect (CDSP; 212140) by Lamhonwah and Tein (1998), see 603377.0005.
In a patient with primary carnitine deficiency (CDSP; 212140), Wang et al. (1999) found homozygosity for a C-to-T transition in exon 5 of the SLC22A5 gene, converting codon 282 from CGA (arg) to TGA (stop). Both parents were heterozygous for the mutation.
Vaz et al. (1999) found the R282X mutation in homozygous state in a patient with classic manifestations of systemic carnitine deficiency. Reintroduction of wildtype OCTN2 cDNA into fibroblasts of the patient by transient transfection restored the cellular carnitine uptake, confirming that mutation in OCTN2 was the cause of the systemic carnitine deficiency.
Burwinkel et al. (1999) identified the R282X mutation in 2 German patients who had different haplotypes, suggesting that this mutation may either be recurrent or an ancient founder mutation. They also found that R282X was associated with a splicing abnormality at the intron 6/exon 7 junction. However, no mutations were present in exon 6, intron 6, or exon 7, suggesting that defective splicing of exon 7 on the R282X allele was due to an unconventional, long-distance mechanism.
In a patient with primary carnitine deficiency (CDSP; 212140), Wang et al. (1999) found compound heterozygosity for a paternal allele containing a 1-bp (A) insertion in exon 7, converting codon 401 from TAT (tyr) to TAA (stop), and a maternal allele containing a 1-bp (G) deletion in exon 8 (603377.0010), causing a frameshift starting at codon 435 (gly) and resulting in a premature termination signal at codon 458.
For discussion of the 1-bp deletion in the SLC22A5 gene that was found in compound heterozygous state in a patient with primary carnitine deficiency (CDSP; 212140) by Wang et al. (1999), see 603377.0009.
For discussion of the pro478-to-leu (P478L) mutation in the SLC22A5 gene that was found in compound heterozygous state in a family with systemic primary carnitine deficiency (CDSP; 212140) by Tang et al. (1999), see 603377.0003.
In 2 unrelated patients with classic systemic carnitine deficiency (CDSP; 212140), Vaz et al. (1999) found homozygosity for the same missense mutation, 632A-G, which changes the tyrosine at amino acid position 211 into a cysteine (Y211C). The first patient had been reported by Rodrigues Pereira et al. (1988) and by Scholte et al. (1990). The second patient was admitted to hospital at 7 months of age because of failure to thrive. Physical examination showed dilated cardiomyopathy. Cardiac decompensation had existed from the age of 5 months. Treatment with digoxin and diuretics was started. At the age of 20 months, she presented with lowered consciousness, respiratory insufficiency, hypoglycemia, hyperammonemia, elevated transaminases, and low plasma carnitine concentrations. With carnitine therapy, improvement of the echocardiographic findings was noted by the age of 2 years. At the age of 5.5 years, the echocardiograph was almost normal.
On 1 of 4 chromosomes from 2 unrelated German patients with systemic primary carnitine deficiency (CDSP; 212140), Burwinkel et al. (1999) identified a G-to-A transition at nucleotide 506 of the SLC22A5 gene, resulting in an arg169-to-gln (R169Q) substitution. The mutation involved an arginine residue absolutely conserved in the entire transporter superfamily to which SLC22A5 belongs. On the 3 other chromosomes, they identified an arg282-to-ter mutation in exon 5 of the gene (R282X; 603377.0008).
Wang et al. (2000) described compound heterozygosity for arg169 to trp (R169W) and trp351 to arg (W351R; 603377.0015) in a patient with systemic primary carnitine deficiency (CDSP; 212140). The patient had presented at 5 years of age with acute metabolic decompensation. The parents were unrelated. This C-to-T transition in exon 2 occurred in a CpG region; therefore, it was not surprising that another patient had a different mutation (R169Q; 603377.0013) in the same residue.
For discussion of the trp351-to-arg (W351R) mutation in the SLC22A5 gene that was found in compound heterozygous state in a patient with systemic primary carnitine deficiency (CDSP; 212140) by Wang et al. (2000), see 603377.0014.
Wang et al. (2001) reported Iranian Jewish sibs with systemic primary carnitine deficiency (CDSP; 212140) who were homozygous for a G-to-A transition at nucleotide 1196 in exon 7 of the SLC22A5 gene, resulting in an arginine-to-glutamine substitution at codon 399 (R399Q). Both parents were heterozygous for this mutation. The first sib presented at 2 years of age in coma during an episode of gastroenteritis, while her older sister had weakness of the proximal limb girdle musculature requiring physical therapy, and developmental delays involving language skills, concentration, and attention span. Starting her on carnitine resulted in marked improvement of muscle tone, general mood, alertness, activity, and concentration span.
This variant, formerly titled INFLAMMATORY BOWEL DISEASE 5, ASSOCIATION WITH, has been reclassified based on the findings of Martinez et al. (2006) and Silverberg et al. (2007).
Peltekova et al. (2004) found a 2-allele haplotype enriched in individuals with Crohn disease (IBD5; 606348) involving a SNP in SLC22A4 (1672C-T; 604190.0002) and G-to-C transversion in the SLC22A5 promoter (-207G-C). The 2-allele risk haplotype was referred to as TC for the nucleotides involved in Crohn disease risk. The TC haplotype was not enriched in individuals with ulcerative colitis.
In a case-control study of 309 Spanish patients with Crohn disease and 408 controls, Martinez et al. (2006) found conflicting evidence for the role of the SLC22A4 1672C-T and the SLC22A5 -207G-C polymorphisms. Separate analysis for each variant showed no disease association, whereas a combination of the 2 variants showed a mildly increased disease risk. The authors suggested that certain haplotypes in defined populations may confer susceptibility or protection to Crohn disease.
Silverberg et al. (2007) evaluated 1,879 affected offspring and parents ascertained by a North American IBD Genetics Consortium for 6 IDB5 SNPs. The findings rejected the previously reported -207G-C SNP as the potential causative variant for Crohn disease susceptibility, although it did not compromise the observation that this SNP may alter SLC22A5 expression.
Dobrowolski et al. (2005) demonstrated a 3G-T transversion in the SLC22A5 gene, predicted to produce a met1-to-ile substitution (M1I), as the cause of systemic primary carnitine deficiency (CDSP; 212140). The causative role of this missense mutation was confirmed by expression in Chinese hamster ovary (CHO) cells.
In 2 unrelated Chinese patients with systemic primary carnitine deficiency (CDSP; 212140), one of whom had previously been described by Marques (1998), Tang et al. (2002) identified homozygosity for a 981C-T transition in exon 4 of the SLC22A5 gene, resulting in an arg254-to-ter (R254X) substitution. The predicted protein has only 5 of the 12 transmembrane domains and is a loss-of-function mutant. Both patients had presented with acute heart failure and dilated cardiomyopathy.
Yamak et al. (2007) identified homozygosity for the R254X mutation in affected members of 2 Lebanese families segregating for primary systemic carnitine deficiency. Their patients shared a common haplotype with the 2 Chinese patients reported by Tang et al. (2002).
Lamhonwah et al. (2004) identified homozygosity for the R254X mutation in a Saudi Arabian girl with systemic carnitine deficiency. Laboratory studies showed impaired fatty acid oxidation and decreased carnitine uptake in skin fibroblasts (less than 1% of control values). Western blot analysis showed absence of the protein. Lamhonwah et al. (2004) stated that the substitution resulted from a 760C-T transition in exon 4.
In an African American family in which an infant was identified as having low carnitine in newborn screening, subsequent analysis showed that the asymptomatic mother actually had systemic carnitine deficiency (CDSP; 212140), with a free plasma carnitine level of 1 micromol/L and a total plasma carnitine of 2 micromol/L. She was found to be compound heterozygous for a C-to-T transversion at nucleotide 1195 of the SLC22A5 gene, resulting in an arg-to-trp substitution at codon 399 (R399W), and a second missense mutation (A442I; 603377.0021).
In an African American family in which an infant was identified as having low carnitine in newborn screening, subsequent analysis showed that the asymptomatic mother actually had systemic carnitine deficiency (CDSP; 212140). She was found to be compound heterozygous for a GC-to-AT substitution at nucleotides 1324/1325 of the SLC22A5 gene, resulting in an ala-to-ile substitution at codon 442 (A442I), and another missense mutation (R399W; 603377.0020).
El-Hattab et al. (2010) identified low carnitine in an Indian infant by newborn screening. Subsequent analysis revealed that his mother had primary carnitine deficiency (CDSP; 212140) with a free plasma carnitine level of 3 micromol/L and total plasma carnitine of 7 micromol/L. She was completely asymptomatic at the age of 33 years. She was homozygous for a G-to-T transversion at nucleotide 43 of the SLC22A5 gene, resulting in a gly-to-trp substitution at codon 15 (G15W).
After finding low carnitine in 2 sibs and their maternal first cousin by newborn screening, Verbeeten et al. (2020) found that their mothers, who were sisters, and a maternal uncle had primary carnitine deficiency (CDSP; 212140) with low plasma carnitine and increased fractional excretion of free carnitine in the urine. Next-generation sequencing identified a homozygous c.-149G-A transition (c.-149G-A, NM_003060) in the SLC22A5 gene in the 3 affected individuals and carrier status in the 3 infants. Skin fibroblast studies from the affected male showed deficient carnitine uptake at less than 6% of control values. Verbeeten et al. (2020) also found that the wife of the affected male was a carrier for the mutation and that 2 of their children were homozygous for the mutation and diagnosed with carnitine uptake deficiency.
In a Pakistani girl, born to first-cousin parents, with primary carnitine deficiency (CDSP; 212140), Perrier et al. (2018) identified a homozygous c.12C-G transversion in the SLC22A5 gene, resulting in a tyr4-to-ter (Y4X) substitution. The mutation was identified by gene sequencing. The patient also had a homozygous mutation in the NDUFA2 gene (602137.0002) and an additional diagnosis of mitochondrial complex I deficiency nuclear type 13 (MC1DN13; 618235).
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