Alternative titles; symbols
HGNC Approved Gene Symbol: HADH
SNOMEDCT: 124122005;
Cytogenetic location: 4q25 Genomic coordinates (GRCh38): 4:107,989,889-108,035,171 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 4q25 | 3-hydroxyacyl-CoA dehydrogenase deficiency | 231530 | Autosomal recessive | 3 |
| Hyperinsulinemic hypoglycemia, familial, 4 | 609975 | Autosomal recessive | 3 |
3-Hydroxyacyl-CoA dehydrogenase (HADH; EC 1.1.1.35) catalyzes the reversible dehydrogenation of 3-hydroxyacyl-CoAs to their corresponding 3-ketoacyl-CoAs with concomitant reduction of NAD to NADH and exerts it highest activity toward 3-hydroxydecanoyl-CoA (He et al., 1989).
L-3-hydroxyacyl-CoA dehydrogenase was first purified from pig heart by Noyes and Bradshaw (1973, 1973). The mature subunit of HADH from pig heart is 302 amino acids long, corresponding to a molecular weight of 33 kD.
Vredendaal et al. (1996) screened a human liver cDNA library with a PCR product obtained by degenerate PCR using primers based on the pig heart HADH amino acid sequence reported by Bitar et al. (1980). Human HADH encodes a deduced 314-amino acid protein composed of a 12-residue mitochondrial import signal peptide and a 302-residue mature HADH protein with a calculated molecular mass of 34.3 kD. The sequence of the mature protein shows 94% identity with HADH from pig heart. Northern blot analysis revealed expression of HADH in liver, kidney, pancreas, heart, and skeletal muscle.
Vredendaal et al. (1998) determined that the human HADH gene contains 8 exons and spans approximately 49 kb.
By fluorescence in situ hybridization, Vredendaal et al. (1996) mapped the human HADH gene to chromosome 4q22-q26.
Pseudogene
Vredendaal et al. (1998) identified a putative HADH pseudogene on chromosome 15q17-q21.
In a patient with HADH deficiency (231530) presenting as fulminant hepatic failure, O'Brien et al. (2000) identified compound heterozygosity for 2 mutations in the HADH gene (601609.0001; 601609.0002).
In patients with hyperinsulinemic hypoglycemia (HHF4; 609975), Clayton et al. (2001) and Molven et al. (2004) identified mutations in the HADH gene (601609.0003, 601609.0004).
In 11 (10%) of 115 unrelated patients with diazoxide-responsive hyperinsulinemic hypoglycemia who were negative for mutation in the hyperinsulinemia-associated genes ABCC8 (600509), KCNJ11 (600937), GCK (138079), and HNF4A (600281), Flanagan et al. (2011) identified homozygous mutations in the HADH gene (see, e.g., 601609.0005 and 601609.0006). When DNA was available, carrier status was confirmed in the unaffected parents; none of the probands had an affected sib.
In a Turkish proband with diazoxide-responsive hyperinsulinemic hypoglycemia mapping to chromosome 4q25, in whom no coding mutation in the HADH gene had been found but who showed a reduction in HADH activity in cultured skin fibroblasts, Flanagan et al. (2013) performed next-generation sequencing of the entire genomic region of HADH and identified homozygosity for a deep intronic splicing variant (636+471G-T; 601609.0007). Screening for the variant in an additional 56 consanguineous and/or Turkish diazoxide-responsive HHF probands revealed homozygosity for 636+471G-T in 8 more Turkish probands. All 9 mutation-positive Turkish patients were also homozygous for the 636+385A-G SNP (rs732941), and 5 of the patients were known to share a 1.6-Mb haplotype at chromosome 4q25. Flanagan et al. (2013) stated that the 636+471G-T Turkish founder mutation was the most common HADH mutation in their cohort and accounted for 9 (32%) of 28 individuals with HADH mutations.
Yang et al. (2005) discussed the confusion in the literature between the nomenclature of 3-hydroxyacyl-CoA dehydrogenase (HADH) and short-chain 3-hydroxyacyl-CoA dehydrogenase (SCHAD; 300256). Although Vredendaal et al. (1996) asserted that 3-hydroxyacyl-CoA dehydrogenase exerted high activity towards 3-hydroxybutyryl-CoA, and thus referred to the enzyme as a 'short-chain' dehydrogenase, He et al. (1989) demonstrated that the enzyme had greater activity for 3-hydroxydecanoyl-CoA, a medium-chain substrate. Yang et al. (2005) stated that the enzyme encoded by the HADH gene should not be referred to as SCHAD. Accordingly, some cases of human metabolic disorders previously reported as 'SCHAD deficiency' (e.g., Tein et al., 1991; Bennett et al., 1996; Treacy et al., 2000; Clayton et al., 2001) are in fact cases of 'HADH deficiency' (231530).
In a patient with HADH deficiency (231530), O'Brien et al. (2000) identified compound heterozygosity for 2 mutations in the HADH gene: a 118G-A transition in exon 1, resulting in an ala28-to-thr (A28T) substitution, and a 171C-A transversion in exon 2, resulting in an asp45-to-glu (D45E; 601609.0002) substitution.
For discussion of the asp45-to-glu (D45E) mutation in the HADH gene that was found in compound heterozygous state in a patient with HADH deficiency (231530) by O'Brien et al. (2000), see 601609.0001.
In an Indian child with severe hyperinsulinemic hypoglycemia (609975), Clayton et al. (2001) identified a homozygous 773C-T transition in exon 7 of the HADH gene, resulting in a pro258-to-leu (P258L) substitution in 1 of the alpha-helices of the C-terminal domain. The mutation was predicted to prevent normal protein folding. In vitro functional expression studies showed that the mutant enzyme had no catalytic activity. The parents were heterozygous for the mutation. Clayton et al. (2001) postulated that the increased insulin secretion in this patient was related to impaired fatty acid oxidation and suggested that a lipid signaling pathway may be involved in the control of insulin secretion by pancreatic beta-cells.
In an inbred Pakistani family previously reported by Vidnes and Oyasaeter (1977) in which 4 sibs, 2 males and 2 females, had hyperinsulinemic hypoglycemia (609975), Molven et al. (2004) demonstrated a 6-bp deletion that removed the acceptor splice site adjacent to exon 5 of the HADH gene. They demonstrated that exon 5 is skipped during the mRNA splicing process, so that exon 4 is coupled directly onto exon 6. This led to an in-frame deletion of 90 nucleotides in the mature mRNA, resulting in a protein product predicted to lack 30 amino acids. Both parents were heterozygous.
In 6 unrelated children with hyperinsulinemic hypoglycemia (HHF4; 609975), 3 from Turkey, 2 from Iran, and 1 from Pakistan, Flanagan et al. (2011) identified homozygosity for a 706C-T transition in exon 6 of the HADH gene, resulting in an arg236-to-ter (R236X) substitution. When DNA was available, carrier status was confirmed in the unaffected parents; none of the probands had an affected sib. Flanagan et al. (2011) noted that the R236X mutation had previously been reported in a patient with hyperinsulinemic hypoglycemia (Di Candia et al., 2009).
In 2 unrelated boys from India with hyperinsulinemic hypoglycemia (HHF4; 609975), Flanagan et al. (2011) identified homozygosity for deletion of the minimal promoter and exon 1 (1-3440_132 + 1943del) in the HADH gene. When DNA was available, carrier status was confirmed in the unaffected parents; neither of the probands had an affected sib.
In 9 Turkish probands with diazoxide-responsive hyperinsulinemic hypoglycemia (HHF4; 609975), 3 of whom were previously studied by Flanagan et al. (2011), Flanagan et al. (2013) identified homozygosity for a 636+471G-T transversion deep within intron 5 of the HADH gene, creating a cryptic splice donor site that results in the inclusion of an out-of-frame 141-bp pseudoexon and premature termination. The mutation was present in heterozygosity in tested parents. All 9 mutation-positive Turkish patients were also homozygous for an HADH SNP, 636+385A-G (rs732941), and 5 of the patients were known to share a 1.6-Mb haplotype at chromosome 4q25 (chr4:108,874,712-108,968,640; GRCh37). Flanagan et al. (2013) stated that the 636+471G-T Turkish founder mutation was the most common HADH mutation in their cohort and accounted for 9 (32%) of 28 individuals with HADH mutations.
Bennett, M. J., Weinberger, M. J., Kobori, J. A., Rinaldo, P., Burlina, A. B. Mitochondrial short-chain L-3-hydroxyacyl-coenzyme A dehydrogenase deficiency: a new defect of fatty acid oxidation. Pediat. Res. 39: 185-188, 1996. [PubMed: 8825408] [Full Text: https://doi.org/10.1203/00006450-199601000-00031]
Bitar, K. G., Perez-Aranda, A., Bradshaw, R. A. Amino acid sequence of L-3-hydroxyacyl CoA dehydrogenase from pig heart muscle. FEBS Lett. 116: 196-198, 1980. [PubMed: 7409145] [Full Text: https://doi.org/10.1016/0014-5793(80)80642-9]
Clayton, P. T., Eaton, S., Aynsley-Green, A., Edginton, M., Hussain, K., Krywawych, S., Datta, V., Malingre, H. E. M., Berger, R., van den Berg, I. E. T. Hyperinsulinism in short-chain L-3-hydroxyacyl-CoA dehydrogenase deficiency reveals the importance of beta-oxidation in insulin secretion. J. Clin. Invest. 108: 457-465, 2001. [PubMed: 11489939] [Full Text: https://doi.org/10.1172/JCI11294]
Di Candia, S., Gessi, A., Pepe, G., Sogno Valin, P., Mangano, E., Chiumello, G., Gianolli, L., Proverbio, M. C., Mora, S. Identification of a diffuse form of hyperinsulinemic hypoglycemia by 18-fluor-L-3,4 dihydroxyphenylalanine positron emission tomography/CT in a patient carrying a novel mutation of the HADH gene. Europ. J. Endocr. 160: 1019-1023, 2009. [PubMed: 19318379] [Full Text: https://doi.org/10.1530/EJE-08-0945]
Flanagan, S. E., Patch, A.-M., Locke, J. M., Akcay, T., Simsek, E., Alaei, M., Yekta, Z., Desai, M., Kapoor, R. R., Hussain, K., Ellard, S. Genome-wide homozygosity analysis reveals HADH mutations as a common cause of diazoxide-responsive hyperinsulinemic-hypoglycemia in consanguineous pedigrees. J. Clin. Endocr. Metab. 96: E498-E502, 2011. [PubMed: 21252247] [Full Text: https://doi.org/10.1210/jc.2010-1906]
Flanagan, S. E., Xie, W., Caswell, R., Damhuis, A., Vianey-Saban, C., Akcay, T., Darendeliler, F., Bas, F., Guven, A., Siklar, Z., Ocal, G., Berberoglu, M., and 9 others. Next-generation sequencing reveals deep intronic cryptic ABCC8 and HADH splicing founder mutations causing hyperinsulinism by pseudoexon activation. Am. J. Hum. Genet. 92: 131-136, 2013. [PubMed: 23273570] [Full Text: https://doi.org/10.1016/j.ajhg.2012.11.017]
He, X.-Y., Yang, S. Y., Schulz, H. Assay of L-3-hydroxyacyl-CoA dehydrogenase with substrates of different chain lengths. Anal. Biochem. 180: 105-109, 1989. [PubMed: 2817332] [Full Text: https://doi.org/10.1016/0003-2697(89)90095-x]
He, X.-Y., Zhang, G., Blecha, F., Yang, S. Y. Identity of heart and liver L-3-hydroxyacyl coenzyme A dehydrogenase. Biochim. Biophys. Acta 1437: 119-123, 1999. [PubMed: 10064895] [Full Text: https://doi.org/10.1016/s1388-1981(98)00005-5]
Molven, A., Matre, G. E., Duran, M., Wanders, R. J., Rishaug, U., Njolstad, P. R., Jellum, E., Sovik, O. Familial hyperinsulinemic hypoglycemia caused by a defect in the SCHAD enzyme of mitochondrial fatty acid oxidation. Diabetes 53: 221-227, 2004. [PubMed: 14693719] [Full Text: https://doi.org/10.2337/diabetes.53.1.221]
Noyes, B. E., Bradshaw, R. A. L-3-hydroxyacyl coenzyme A dehydrogenase from pig heart muscle. I. Purification and properties. J. Biol. Chem. 248: 3052-3059, 1973. [PubMed: 4700451]
Noyes, B. E., Bradshaw, R. A. L-3-hydroxyacyl coenzyme A dehydrogenase from pig heart muscle. II. Subunit structure. J. Biol. Chem. 248: 3060-3066, 1973.
O'Brien, L. K., Rinaldo, P., Sims, H. F., Alonso, E. M., Charrow, J., Jones, P. M., Bennett, M. J., Barycki, J. J., Banaszak, L. J., Strauss, A. W. Fulminant hepatic failure associated with mutations in the medium and short chain L-3-hydroxyacyl-CoA dehydrogenase gene. (Abstract) J. Inherit. Metab. Dis. 23 (suppl. 1): 127 only, 2000.
Tein, I., De Vivo, D. C., Hale, D. E., Clarke, J. T. R., Zinman, H., Laxer, R., Shore, A., DiMauro, S. Short-chain L-3-hydroxyacyl-CoA dehydrogenase deficiency in muscle: a new case for recurrent myoglobinuria and encephalopathy. Ann. Neurol. 30: 415-419, 1991. [PubMed: 1835339] [Full Text: https://doi.org/10.1002/ana.410300315]
Treacy, E. P., Lambert, D. M., Barnes, R., Boriack, R. L., Vockley, J., O'Brien, L. K., Jones, P. M., Bennett, M. J. Short-chain hydroxyacyl-coenzyme A dehydrogenase deficiency presenting as unexpected infant death: a family study. J. Pediat. 137: 257-259, 2000. [PubMed: 10931422] [Full Text: https://doi.org/10.1067/mpd.2000.107467]
Vidnes, J., Oyasaeter, S. Glucagon deficiency causing severe neonatal hypoglycemia in a patient with normal insulin secretion. Pediat. Res. 11: 943-949, 1977. [PubMed: 904979] [Full Text: https://doi.org/10.1203/00006450-197709000-00001]
Vredendaal, P. J. C. M., van den Berg, I. E. T., Malingre, H. E. M., Stroobants, A. K., Olde Weghuis, D. E. M., Berger, R. Human short-chain L-3-hydroxyacyl-CoA dehydrogenase: cloning and characterization of the coding sequence. Biochem. Biophys. Res. Commun. 223: 718-723, 1996. [PubMed: 8687463] [Full Text: https://doi.org/10.1006/bbrc.1996.0961]
Vredendaal, P. J. C. M., van den Berg, I. E. T., Stroobants, A. K., van der A, D. L., Malingre, H. E. M., Berger, R. Structural organization of the human short-chain L-3-hydroxyacyl-CoA dehydrogenase gene. Mammalian Genome 9: 763-768, 1998. [PubMed: 9716664] [Full Text: https://doi.org/10.1007/s003359900860]
Yang, S.-Y., He, X.-Y., Schulz, H. 3-Hydroxyacyl-CoA dehydrogenase and short chain 3-hydroxyacyl-CoA dehydrogenase in human health and disease. FEBS J. 272: 4874-4883, 2005. [PubMed: 16176262] [Full Text: https://doi.org/10.1111/j.1742-4658.2005.04911.x]