Alternative titles; symbols
HGNC Approved Gene Symbol: ACADM
SNOMEDCT: 128596003; ICD10CM: E71.311;
Cytogenetic location: 1p31.1 Genomic coordinates (GRCh38) : 1:75,724,709-75,763,679 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 1p31.1 | Acyl-CoA dehydrogenase, medium chain, deficiency of | 201450 | Autosomal recessive | 3 |
Matsubara et al. (1986) stated that 5 acyl-CoA dehydrogenases had been reported: short-chain (606885), medium-chain (EC 1.3.99.3), and long-chain (609576) acyl-CoA dehydrogenases; isovaleryl-CoA dehydrogenase (243500); and 2-methyl branched-chain acyl-CoA dehydrogenase. The first 3 catalyze the initial reaction in the beta-oxidation of fatty acids, while the last 2 catalyze the dehydrogenation of branched short-chain acyl-CoAs in the metabolism of the branched-chain amino acids. All 5 may have evolved from a common ancestral gene.
By screening a liver cDNA library with the rat pre-medium-chain acyl-CoA dehydrogenase cDNA, Matsubara et al. (1986) cloned a partial human MCAD cDNA. The MCAD enzyme is a homotetramer with a molecular mass of about 45 kD.
Kelly et al. (1987) determined the MCAD mRNA nucleotide sequence from 2 overlapping cDNA clones isolated from human liver and placenta cDNA libraries, respectively. The sequence encodes a 421-amino acid protein with characteristics of mitochondrial protein transit peptides. The protein shows 88% sequence identity with porcine MCAD.
The MCAD gene contains 12 exons (Zhang et al., 1992).
Medium-chain acyl-CoA dehydrogenase catalyzes the initial reaction in the beta-oxidation of C4 to C12 straight-chain acyl-CoAs (Matsubara et al., 1986).
Matsubara et al. (1986) mapped the ACADM gene to 1p31 by Southern analysis of DNA from hybrid cells and by in situ hybridization. Kidd et al. (1990) demonstrated extensive polymorphism in ACADM. With linkage studies, they showed that the ACADM locus is proximal to PGM1 (171900). Since the latter locus has been assigned to 1p22.1 by somatic cell studies, these results are in conflict with the assignment of ACADM to 1p31 by in situ hybridization. The authors suggested that the somatic cell localization of PGM1 may be incorrect.
By use of a backcross with Mus spretus, Bahary et al. (1991) assigned the homologous gene to chromosome 8 in the mouse. However, Tolwani et al. (1996) mapped the Acadm gene to the distal end of mouse chromosome 3. They showed that sequences previously localized to chromosome 8 represent a pseudogene, and identified an additional pseudogene on chromosome 11.
Kelly et al. (1987) performed blot hybridization of RNA prepared from cultured skin fibroblasts from a patient with MCAD deficiency (ACADMD; 201450) and showed that mRNA was present and of similar size to MCAD mRNA derived from control fibroblasts.
In 9 patients with MCAD deficiency, Matsubara et al. (1990) identified a homozygous 985A-G transition in the MCAD gene, which resulted in a lys304-to-glu substitution (K304E; 607008.0001) in the mature protein. These patients were unrelated, suggesting a high incidence of this abnormality among Caucasian patients. The change was not found in 20 healthy Caucasian and 6 healthy Japanese subjects. Matsubara et al. (1990) found this point mutation in 31 of 34 (91%) mutant MCAD alleles.
Zschocke et al. (2001) characterized the molecular defect in 4 patients with mild MCAD deficiency. In routine neonatal screening on the fifth day of life, they had been found to have abnormal acylcarnitine profiles indicative of MCAD deficiency. Two were of German origin and the other 2 were born to different consanguineous Turkish parents. In all 4, the clinical course and routine laboratory investigations up to the age of 6 months were unremarkable. Enzyme studies showed residual MCAD activities between those with classic MCAD deficiency and heterozygotes. In 2 cases, ACADM gene analysis revealed compound heterozygosity for the common K304E mutation (607008.0001) and the Y42H mutation (607008.0011), which they designated Y67H. In the 2 children of consanguineous parents, homozygosity was found for the gly267-to-arg mutation (G267R; 607008.0003) and the S220L mutation (607008.0012), respectively. As in other metabolic disorders, the distinction between 'normal' and 'disease' in MCAD deficiency is blurred into a spectrum of enzyme deficiency states caused by different mutations in the ACADM gene potentially influenced by factors affecting intracellular protein processing.
Wilcken et al. (2003) reported on the use of electrospray tandem mass spectrometry to screen newborns for 31 inborn errors affecting the metabolism of the urea cycle, amino acids, and organic acids and fatty acid oxidation in a 4-year period in Australia. The rate of inborn errors, excluding PKU, was 15.7 per 100,000 births, as compared with adjusted rates of 8.6 to 9.5 per 100,000 births in the 4 preceding 4-year cohorts. The rate of detection was increased specifically for MCAD deficiency and other disorders of fatty acid oxidation, as compared with the 16-year period before the implementation of neonatal screening for these disorders.
Maier et al. (2009) analyzed the impact of 10 ACADM mutations (see, e.g., 607008.0001 and 607008.0011) on conformation, stability and enzyme kinetics of the corresponding mutant proteins. Partial to total rescue of aggregation by overexpression of GroES (HSPE1; 600141) and GroEL (HSPD1; 118190) suggested protein misfolding as a pathogenic mechanism. Catalytic function varied from high residual activity to markedly decreased activity or substrate affinity. Mutations mapping to the beta-domain of the protein predisposed to severe destabilization. In silico structural analysis of the affected amino acid residues revealed involvement in functionally relevant networks. Maier et al. (2009) concluded that protein misfolding with loss-of-function is the common molecular basis in MCAD deficiency.
Suhre et al. (2011) reported a comprehensive analysis of genotype-dependent metabolic phenotypes using a GWAS with nontargeted metabolomics. They identified 37 genetic loci associated with blood metabolite concentrations, of which 25 showed effect sizes that were unusually high for GWAS and accounted for 10 to 60% differences in metabolite levels per allele copy. These associations provided new functional insights for many disease-related associations that had been reported in previous studies, including those for cardiovascular and kidney disorders, type 2 diabetes, cancer, gout, venous thromboembolism, and Crohn disease. Suhre et al. (2011) identified rs211718 in the ACADM gene as associated with hexanoylcarnitine/oleate ratio with a p value of 2.2 x 10(-71).
Tajima et al. (2016) sequenced the ACADM gene in a cohort of 31 Japanese patients with MCAD deficiency and 7 Japanese carriers of MCAD deficiency. The most prevalent mutation was a 4-bp deletion (c.449_452delCTGA; 607008.0016) identified in 25 ACADM alleles of 22 subjects from 19 families. Other prevalent mutations in this cohort included R17H, G362E, R53C, and R281S. These 5 mutations accounted for 60% of the mutations identified in this patient cohort.
Andresen et al. (1997) determined the frequency of 14 known and 7 previously unknown non-G985 mutations in the MCAD gene in 52 families with MCAD deficiency not caused by homozygosity for the prevalent G985 mutation. They showed that none of the non-G985 mutations is prevalent. In 14 families in which they identified both disease-causing mutations, they correlated the mutations with clinical/biochemical data and found that a genotype/phenotype correlation in MCAD deficiency is not straightforward.
This mutation has also been called LYS329GLU (K329E), based on the precursor protein.
In 9 patients with MCAD deficiency (ACADMD; 201450), Matsubara et al. (1990) identified an A-to-G transition in the ACADM gene, which resulted in the substitution of lysine (AAA) by glutamic acid (GAA) at residue 329 (K304E) of the enzyme. These patients were unrelated, suggesting a high instance of this abnormality among Caucasian patients. The change was not found in 20 healthy Caucasian and 6 healthy Japanese subjects. Matsubara et al. (1990) found this point mutation in 31 of 34 (91%) mutant MCAD alleles.
In 3 patients with MCAD deficiency, Yokota et al. (1990) demonstrated an A-to-G transition at position 985 (G985) of the coding region of the ACADM gene, which resulted in a lys304-to-glu (K304E) substitution in the mature protein. Since no appropriate restriction sites for detecting this point mutation were found, they devised an ingenious PCR-based method for demonstrating the G985 mutation. In studies of 9 MCAD deficient patients, homozygosity for this mutation was found in all; in contrast, all 8 controls lacked the mutation. All the patients were Caucasian. In a later study, Yokota et al. (1990) found that the mutation introduces a new NcoI restriction site. Genomic DNA from 11 unrelated MCAD patients was homozygous for the G985 transition as indicated by complete cleavage of PCR-amplified fragments by NcoI. The high prevalence of this mutation in Caucasians and the similarity between the mutations described by Yokota et al. (1990) and Matsubara et al. (1990) suggested that the distinction may lie simply in the numbering of residues and that in fact the investigators had described the same mutation. (Residue 304 in the mature human MCAD corresponds to residue 329 in the preprotein.) Yokota et al. (1990) stated that only 3 patients overlapped in their study and that of Matsubara et al. (1990).
In a Dutch MCAD-deficient patient described by Duran et al. (1986), Kelly et al. (1990) found an A-to-G change at nucleotide 985 of the MCAD mRNA coding region, resulting in substitution of glutamic acid for lysine at amino acid 304 of the mature protein. In addition to the point mutation, a significant proportion of the index patient's MCAD mRNA contained a variety of deletions and insertions as a result of exon skipping and intron retention. The missplicing occurred in multiple regions throughout the MCAD mRNA. Analysis of regions where missplicing occurred most frequently did not reveal a mutation in the splice acceptor or donor sites. That the lys304-to-glu mutation was pathogenic was supported by the fact that the change was not found in any wildtype MCAD mRNAs. Using a PCR-based test on consecutive Guthrie spots, Blakemore et al. (1991) studied the frequency of the G985 MCAD mutation in the neonatal population of the Trent (England) health region. Although no homozygotes were found, 6 of 410 newborns were heterozygous for the mutation, representing a carrier frequency of 1 in 68. This suggests that the frequency of homozygotes should be about 1 in 18,500 births. Since about 15% of mutations are other than the G985 mutation, the total carrier frequency may be 1 in 58, with the total population frequency 1 in 13,400. Gregersen et al. (1991) found the same mutation in homozygous form in 12 of 13 patients with MCAD deficiency. Gregersen et al. (1991) later reported that 15 of 16 patients with MCAD deficiency were homozygous for the G985 mutation. The same 15 who were homozygous for G985 were also homozygous for the haplotype 112, suggesting founder effect. Kolvraa et al. (1991) found the G985 mutation in 31 of 32 disease-causing alleles. In at least 30 of the 31 alleles carrying this G985 mutation, a specific RFLP haplotype was found. In contrast, the same haplotype was present in only 23% of normal alleles. The findings were interpreted as consistent with a strong founder effect. Curtis et al. (1991) studied 21 affected children from 18 families in the U.K. In 14 families the children were homozygous for the G985 mutation. In 3 families the children were compound heterozygotes for G985 and another unknown mutation. In 1 family the affected child did not carry the G985 on either chromosome. It was calculated that the carrier incidence of the G985 mutation is 1 in 68.
In a study of 55 MCAD-deficient patients, Yokota et al. (1991) reported that the G985 allele was found in homozygous state in 44 and in heterozygous state in 10; one patient did not carry this mutant allele, indicating that the prevalence of the G985 allele was 89.1%. They identified 5 other types of mutations: one each in 3 of the compound heterozygotes and 2 in the single non-G985 patient. A RFLP study of 12 G985-homozygotes showed that all 24 alleles fell into a single haplotype. All of 41 patients for whom information was available were Caucasians. Of 29 patients whose country of origin was specified, 19 were from the British Isles and 5 from Germany. Yokota et al. (1991) interpreted these data to indicate that the G985 mutation may have occurred in a single person in an ancient Germanic tribe.
Ding et al. (1991) analyzed DNA from 7 infants who had died suddenly of unexpected causes, i.e., cases of sudden infant death syndrome (SIDS; 272120). These cases were identified through the diagnosis of MCAD deficiency in subsequent, live sibs. Mutational analysis performed on postmortem fixed tissue showed the A-to-G mutation at nucleotide 985 in homozygous form in all 7 probands and in heterozygous form in all parents. The fixed tissues had been stored for as long as 18 years. Miller et al. (1992) extracted DNA from autopsy tissues of 67 victims of SIDS in Monroe County, N.Y., who died between 1984 and 1989. Using the PCR/NcoI digestion method, they found no G985 homozygotes and 3 (4.5%) G985 heterozygotes. In 70 newborn controls, they found no G985 homozygotes and 1 (1.4%) heterozygote. They doubted that the G985 mutation is strongly associated with SIDS. Opdal et al. (1995) found no case of the G985 mutation among 133 cases of SIDS, 6 cases of borderline SIDS, and 30 cases of infectious death in Norway.
Leung et al. (1992) described an affected neonate in whom lethargy and hypotonia developed at 46 hours of age and death followed 10 hours later. They claimed that neonatal presentation had been ignored or discounted in literature reviews.
Matsubara et al. (1991) determined the prevalence of the K304E mutation by study of dried blood spots on Guthrie cards obtained in neonatal screening programs. Twelve carriers were identified among 479 newborn babies in Britain, 5 among 353 in Australia, 5 among 536 in North America, but none among 500 samples in Japan. Gregersen et al. (1991) described a PCR-based assay suitable for use with Guthrie spots. See Matsubara et al. (1992) for a review.
Yokota et al. (1992) estimated that 90% of MCAD cases involve a substitution of lysine-329 in the precursor (lysine-304 in the mature protein). Yokota et al. (1992) used site-directed mutagenesis to produce 3 variant cDNAs encoding variant precursor MCAD with glutamate, aspartate, or arginine substituted for lys329. They carried out in vitro expression studies of the cDNAs, and incubated the translation products with isolated rat liver mitochondria. K329E precursor was imported into mitochondria and processed into the mature subunit as efficiently as wildtype, but 10 minutes after import markedly more K329E eluted as a monomer than did wildtype, and the amount of K329E tetramer formed was distinctly less than wildtype at any point up to 60 minutes after import, indicating that the assembly of K329E was defective. After further incubation, K304E decayed more rapidly than did wildtype, indicating a reduced stability. In similar studies K329R behaved like the wildtype, while K329D closely resembled K329E, indicating that a basic residue at 304 is essential for tetramer formation and intramitochondrial stability of mature MCAD.
Gregersen et al. (1993) found that the frequency of G985 heterozygotes in Caucasians in North Carolina is 1 in 84 (there are many Scottish-Irish in North Carolina), which is 5- to-10-fold higher than the frequency found in non-Caucasian Americans. They also found a complete association of the G985 mutation in 17 families with a certain haplotype. The frequency of G985 mutation carriers was 1 in 68 to 1 in 101 in newborns in the United Kingdom and Denmark, but 1 in 333 in Italy. They interpreted this as indicating a founder effect in northwestern Europe.
A prevalence of carriers of 1 in 55 was estimated by de Vries et al. (1996) on the basis of study of Guthrie cards of newborns. Comparably, the glu510-to-gln mutation of the HADHA gene (600890.0001) is responsible for some 87% of cases of long-chain 3-hydroxyacyl-CoA dehydrogenase (LCHAD) deficiency (IJlst et al., 1996).
Wang et al. (1999) provided data on the frequency of the K304E mutation in 20 countries. Of patients clinically diagnosed with MCADD, 81% had been identified retrospectively as homozygous for K304E, and 18% were compound heterozygotes for K304E. The frequency varied from 1 in 6,400 in Birmingham, England, and 1 in 10,000 in Finland to 1 in 442,000 in Italy.
In 7 newborns, Andresen et al. (2001) found compound heterozygosity for a 199T-C transition in exon 3 of the ACADM gene, causing a tyr42-to-his substitution. This mutation had never been observed in clinically manifest disease, but was present in a large proportion of the acylcarnitine-positive samples. Overexpression Screening programs employing analysis of acylcarnitines in blood spots by tandem mass spectrometry (MS/MS) are widely used for screening for MCAD deficiency. Andresen et al. (2001) performed mutation analysis in blood spots from 930,078 neonates in the U.S. and found a frequency of MCAD deficiency of 1 in 15,001. Mutation analysis showed that the frequency of the 985A-G mutant allele in newborns with a positive acylcarnitine profile was much lower than that observed in clinically affected patients.
In 4 asymptomatic sibs, Albers et al. (2001) reported compound heterozygosity for an arg256-to-thr substitution (607008.0013) with K304E.
Bodman et al. (2001) reported a 12-month-old child who presented with viral infections and lethargy and was found to be homozygous for the 985A-G mutation. Family history revealed that his father had experienced episodes of hypoglycemic shock, and genetic analysis showed that he also was homozygous for the mutation. The authors noted that the carrier frequency for the mutation is as common as 1 in 55 persons, which predicts a homozygote frequency of 1 in 12,000.
Nichols et al. (2008) found that the K304E mutation accounted for only 47.5% of mutant ACADM alleles in New York state over an 18-month period of newborn screening. The frequency was lower than that reported by others, possibly reflecting the mixed ethnic composition of the New York population. Y42H (607008.0011) was the second most common mutation, accounting for 7.5% of mutant alleles.
In a meta-regression analysis of 43 studies reporting the frequency of the c.985A-G mutation in over 10 million individuals, Leal et al. (2014) found significant variation in the frequency of the mutation across regions. The proportion of individuals homozygous for the mutation was highest in western Europe (4.1 per 100,000), followed by the New World, including the United States, Canada, and Australia (3.2), southern Europe (1.2), and eastern Europe (0.9). No cases with the mutation were identified in Asia or the Middle East. The findings were consistent with a founder effect originating in northern Europe.
In a Spanish patient with MCAD deficiency (ACADMD; 201450), who was previously described by Del Valle et al. (1984), Yokota et al. (1990, 1991) found compound heterozygosity for the mutation listed here as 607008.0001 and an apparently rare mutant allele consisting of a 13-bp tandem repeat from position 999 (T) to 1011 (C) in the MCAD cDNA sequence, causing a premature stop codon at the 5-prime end of the second set of the repeat (after tyr337).
Yokota et al. (1991) found a G-to-A transition at position 799 in the ACADM gene in 2 of 110 mutant alleles studied.
Yokota et al. (1991) found a T-to-C transition at position 1124 in the ACADM gene as the responsible mutation in 1 of 110 mutant alleles.
In 1 patient out of 55 with MCAD deficiency (201450), Yokota et al. (1991) found compound heterozygosity in the ACADM gene, with 1 allele having a transition from T-to-C at position 730, resulting in substitution of arginine for cysteine-244. Thus this allele represented only 1 out of 110 studied.
In a study of 55 patients with MCAD deficiency (ACADMD; 201450), Yokota et al. (1991) found a G-to-A transition at position 447 in the ACADM gene in 1 of 110 mutant alleles. The mutation resulted in substitution of isoleucine for methionine-149.
Ding et al. (1992) found a deletion of nucleotides 1102-1105, inclusive, from MCAD cDNA. The patient was a compound heterozygote for this allele and the lys329-to-glu mutation (607008.0001). The 4-bp deletion came from paternal Welsh ancestry. Kelly et al. (1992) identified the same 4-bp deletion in compound heterozygous state with the same lys329-to-glu mutation.
In an infant with MCAD deficiency (ACADMD; 201450), Ziadeh et al. (1995) demonstrated compound heterozygosity for the common lys329-to-glu mutation (607008.0001) and a previously undescribed mutation: a deletion of 6 amino acids which removed gly90 and cys91 from the MCAD protein.
MCAD deficiency (ACADMD; 201450) typically presents in the second year of life as hypoketotic hypoglycemia associated with fasting and may progress to liver failure, coma, and death. Most cases (approximately 80%) are homozygous for the lys329-to-glu mutation in the ACADM gene (607008.0001). Brackett et al. (1994) reported 4 compound heterozygous individuals from 2 unrelated families with the lys329-to-glu mutation on 1 allele and a novel G-to-A transition at nucleotide 583 as the second mutant allele. These patients presented with MCAD deficiency in the first week of life. The expressed 583G-A mutant protein lacked enzymatic activity. The novel mutation was associated with severe MCAD deficiency causing hypoglycemia or sudden unexpected neonatal death. The mutation predicts a change from glycine, a neutral amino acid with no side chain, to arginine, a positively charged residue with a bulky side chain, at amino acid 195 (G170R) of the precursor protein (residue 170 of the mature protein). This amino acid is conserved as a small neutral amino acid (glycine or alanine) in every known acyl-CoA dehydrogenase.
Andresen et al. (1997) studied 52 families with MCAD deficiency (201450) not caused by homozygosity for the K304E mutation (607008.0001) and found 7 new mutations in the ACADM gene. One of these was a 577A-G point mutation resulting in a thr168-to-ala amino acid substitution in the mature protein. The patient and his father had previously been reported to be heterozygous for a 13-bp insertion mutation in exon 11; the mother was found to be heterozygous for the 577A-G mutation. The steady-state amounts of MCADH mRNA from both mutant alleles were found to be decreased. Kuchler et al. (1999) stated that what set the T168A mutation apart from all other previously known mutations was that it constituted the first case of a modification within the active site of the protein. Thr168 is located in contact with the FAD cofactor and forms a hydrogen-bond with the flavin N(5) position. This is the point of entry of the substrate-derived hydride during catalysis, so that it is conceivable that the modification affects the chemistry of catalysis. Kuchler et al. (1999) investigated these aspects and reported on some of the properties of the mutant protein in comparison with those of wildtype MCADH and K304E-MCADH.
This mutation has also been called TYR67HIS (Y67H).
In 7 newborns with MCAD deficiency (201450), Andresen et al. (2001) identified a new mutation in the ACADM gene, a 199T-C change resulting in a tyr42-to-his (Y42H) substitution. Although this mutation had never been observed in patients with clinically manifest disease, it was present in a large proportion of the acylcarnitine-positive samples. The Y42H mutation was found to have a carrier frequency of 1 in 500 in the general population, and overexpression experiments showed that it is a mild folding mutation that exhibits decreased levels of enzyme activity only under stringent conditions. In all cases in which haplotyping was performed, the 199T-C mutation was found on the same haplotype, indicating a common origin of the mutant allele.
In 2 patients with MCAD deficiency, Zschocke et al. (2001) found the same mutation, which they called a tyr67-to-his mutation. The mutation was found in compound heterozygosity with the K329E mutation (607008.0001) in both patients.
By in vitro studies, O'Reilly et al. (2004) determined that the Y42H mutation compromised enzyme activity to only a minor degree. Substrate binding, interaction with the natural electron acceptor, and binding of the prosthetic group FAD were only slightly affected by the Y42H mutation. However, thermostability of the Y42H variant was decreased compared to wildtype protein but not to the same degree as that of the K304E variant. The findings suggested that Y42H is a temperature-sensitive mutation, which is mild at low temperatures, but may have deleterious effects at increased temperatures.
Nichols et al. (2008) found that Y42H was the second (7.5%) most common ACADM mutation in New York state over an 18-month period of newborn screening. K304E was most common, accounting for 47.5% of mutant ACADM alleles.
This mutation has also been called SER245LEU (S245L), based on the precursor protein.
In a patient with MCAD deficiency (201450), Zschocke et al. (2001) found a homozygous C-to-T transition at nucleotide 734 in exon 9 of the ACADM gene, resulting in a ser220-to-leu (S220L) mutation.
Albers et al. (2001) reported a G-to-C transversion at nucleotide 842 in the ACADM gene, resulting in an arg256-to-thr substitution. This mutation was found in compound heterozygosity with the lys304-to-glu mutation (607008.0001) in 4 asymptomatic sibs, ranging in age from 1 to 9 years, with MCAD deficiency (201450). The proband was identified because of expanded newborn screening using tandem mass spectrometry. Albers et al. (2001) suggested that this mutation may have a mild or benign clinical phenotype and that it is important to screen older unscreened sibs of all infants diagnosed by expanded newborn screening.
Andresen et al. (2001) initially reported the 362C-T mutation in the ACADM gene in a baby with MCAD deficiency (201450) identified in a U.S. MS/MS newborn screening program and demonstrated that the encoded T96I mutant ICAD protein had a low but detectable level of enzyme activity. Thereafter the same mutation was identified in 2 additional newborns and in 3 patients with clinically manifest disease.
Nielsen et al. (2007) showed that mRNA from alleles with the 362C-T mutation displayed a high level of exon 5 skipping. Exon 5 skipping led to a shifted reading frame, resulting in a premature termination codon in exon 6, indicating that the decreased amount of MCAD mRNA from the 362C-T allele is a result of nonsense-mediated decay (NMD). The authors went on to demonstrate that the MCAD 362C-T mutation disrupts an exonic splicing enhancer (ESE). They concluded that the MCAD ESE is functionally similar to the ESE of SMN1 (600354). Further studies demonstrated that the negative effect of the 362C-T mutation is antagonized by a flanking polymorphic 351A-C synonymous variation (607008.0015). In conclusion, Nielsen et al. (2007) reported a novel mechanism by which a presumed neutral polymorphic variant, 351C, in an exon can protect against disease-causing splicing mutations. This could be a common mode by which SNPs affect gene expression, but, under normal conditions, such occurrences would be underestimated because the involved ESS elements would be unmasked only when the mutation in cis inactivates the antagonizing ESE element. Nielsen et al. (2007) suggested that this mechanism may also play an important role in evolution, since substitutions that inactivate such ESS elements would neutralize the restrictions put on splicing-inactivating mutations elsewhere in the exon.
Nielsen et al. (2007) identified a neutral polymorphic variant in exon 5 of the ACADM gene, 351A-C, that inactivates the exonic splicing silencer (ESS) and, while this has no effect on splicing itself, makes splicing immune to deleterious mutations in the ESE.
In a cohort of 31 Japanese patients with MCAD deficiency and 7 Japanese carriers of the disorder (ACADMD; 201450), Tajima et al. (2016) found that the most prevalent mutation was a 4-bp deletion (c.449_452delCTGA) in the ACADM gene, predicted to result in a frameshift and premature termination (Thr150Argfs). The mutation, which was found by direct sequencing of the gene, was identified in 25 ACADM alleles of 22 individuals from 19 families. Analyses in patient lymphocytes showed that the mutation resulted in abolished ACADM enzyme activity.
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