Alternative titles; symbols
HGNC Approved Gene Symbol: OGDHL
Cytogenetic location: 10q11.23 Genomic coordinates (GRCh38): 10:49,734,641-49,762,379 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 10q11.23 | Yoon-Bellen neurodevelopmental syndrome | 619701 | Autosomal recessive | 3 |
OGDHL is predicted to be a thiamine diphosphate-dependent 2-oxo acid dehydrogenase (EC 1.2.4.2) for reduction of protein-bound lipoyl groups (Bunik and Degtyarev, 2008).
OGDHL encodes a rate-limiting enzyme in the Krebs cycle that plays a pivotal role in mitochondrial metabolism (Yap et al., 2021).
By sequencing clones obtained from a size-fractionated adult human brain cDNA library, Nagase et al. (1999) cloned OGDHL, which they designated KIAA1290. The deduced 1,011-amino acid protein shares 79% identity with human 2-oxoglutarate dehydrogenase E1 component precursor (DHTKD1; 614984). Database analysis identified the C. elegans ortholog of KIAA1290. RT-PCR ELISA detected strong KIAA1290 expression in adult brain and kidney, followed by liver and fetal brain. Moderate KIAA1290 expression was detected in adult spinal cord, pancreas, testis, and ovary, and in fetal liver. Little to no KIAA1290 expression was detected in adult lung, skeletal muscle, or spleen. Moderate to high KIAA1290 expression was detected in all adult human brain regions examined.
Bunik and Degtyarev (2008) determined that human OGDHL has a cleavable N-terminal mitochondrial localization signal and domains characteristics of a 2-oxo acid dehydrogenase, including a GxxxG lipid-binding motif, thiamine diphosphate-binding motif, potassium-binding domains, and 3 catalytic activation loops.
Sen et al. (2012) colocalized OGDHL with OGDH (613022) in mitochondria in human cervical cancer cell lines.
Using overexpression and knockdown studies in human cervical cancer cell lines, Sen et al. (2012) found that OGDHL increased lipid peroxidation and production of reactive oxygen species. Consequently, OGDHL inhibited cell growth and migration, and caused apoptosis through caspase-3 (CASP3; 600636)-mediated inactivation of the AKT (see 164730) signaling cascade. OGDHL also directly bound NF-kappa-B (see 164011) and reduced its DNA-binding and transcriptional activity.
By radiation hybrid analysis, Nagase et al. (1999) mapped the OGDHL gene to chromosome 10.
Bunik and Degtyarev (2008) reported that the OGDHL gene maps to chromosome 10q11.23.
In a 15-year-old girl (BAB4852), born of consanguineous Turkish parents, with Yoon-Bellen neurodevelopmental syndrome (YOBELN; 619701), Yoon et al. (2017) identified a homozygous missense mutation in the OGDHL gene (S778L; 617513.0001). The mutation, which was identified in a large database of patients who underwent exome sequencing, segregated with the disorder in the family. Studies using mutant Drosophila with loss of Ogdh (613022), orthologous to human OGDHL, indicated that the OGDHL variant resulted in a loss of function.
In 9 patients from 8 unrelated families of various ethnic descent with YOBELN, Yap et al. (2021) identified homozygous or compound heterozygous mutations in the OGDHL gene (see, e.g., 617513.0002-617513.0006). The patients were ascertained through the GeneMatcher program after exome sequencing identified the variants. Most of the mutations were confirmed by Sanger sequencing; the mutations segregated with the disorder in the families. There was 1 frameshift, 1 nonsense, and 1 splice site mutation; the remaining mutations were missense variants affecting conserved residues throughout the gene. Detailed in vitro studies of the orthologous missense mutations expressed in Drosophila indicated that some caused a loss of function with decreased protein levels, whereas others conferred normal protein levels. None of the missense variants were able to rescue the lethality of Ogdh-null Drosophila, indicating that they are loss-of-function alleles. In addition, some of the variants tested were unable to rescue lethality in flies with neuronal-specific expression of the mutations, whereas others caused mild behavioral defects in flies. The overall findings indicated that some of the missense mutations resulted in severe functional OGDHL deficiency, whereas others had a less severe effect and acted as hypomorphic alleles. Loss of OGDHL in human neuroblastoma cells resulted in defects in the Krebs cycle and mitochondrial metabolism.
In a 15-year-old girl (BAB4852), born of consanguineous Turkish parents, with Yoon-Bellen neurodevelopmental syndrome (YOBELN; 619701), Yoon et al. (2017) identified a homozygous c.2333C-T transition (c.2333C-T, NM_018245) in exon 18 of the OGDHL gene, resulting in a ser778-to-leu (S778L) substitution at a conserved region in the transketolase domain. The mutation, which was identified in a large database of patients who underwent exome sequencing, segregated with the disorder in the family. Studies using mutant Drosophila with loss of Ogdh (613022), orthologous to human OGDHL, indicated that the OGDHL variant resulted in a loss of function. The patient had developmental delay apparent in the first year of life, with inability to walk, spasticity, ataxia, microcephaly, and language problems. She did not have seizures. Brain imaging showed hypoplasia of the corpus callosum, cerebellar volume loss, and enlarged ventricles. A similarly affected sib died at age 28 years after being bedridden for many years.
Yap et al. (2021) found that expression of the orthologous Drosophila mutant (S793L) in Drosophila neurons resulted in increased protein levels compared to controls, suggesting that the mutation may lead to abnormal accumulation of misfolded protein aggregates.
In 2 sibs (P1 and P2), born of consanguineous Iranian parents, with Yoon-Bellen neurodevelopmental syndrome (YOBELN; 619701), Yap et al. (2021) identified a homozygous c.2554C-G transversion (c.2554C-G, NM_018245) in the OGDHL gene, resulting in a pro852-to-ala (P852A) substitution at a conserved residue. The mutation, which was found by exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. It was not present in the gnomAD database. Functional studies of patient cells were not performed, but transfection of the orthologous mutation in Drosophila (P867A) indicated that it was expressed at normal levels. However, expression of the mutation was unable to rescue lethality in Ogdh-null Drosophila, consistent with a loss of function. The patients, who were 7 and 16 years of age, presented in infancy with profound hearing loss followed by mild developmental delay and learning difficulties. One had a single seizure at age 7 years.
In a 27-year-old Italian man (P3) with Yoon-Bellen neurodevelopmental syndrome (YOBELN; 619701), Yap et al. (2021) identified compound heterozygous mutations in the OGDHL gene: a homozygous c.2018G-A transition (c.2018G-A, NM_018245), resulting in an arg673-to-gln (R673Q) substitution at a conserved residue, and a c.1464T-C transition (617513.0004) predicted to result in a synonymous val488-to-val (V488V) substitution, although in vitro studies of patient cells showed that it resulted in a splicing defect. The mutations, which were found by exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. Neither was present in the gnomAD database. Functional studies of patient cells were not performed, but expression of the orthologous missense mutation in Drosophila (R688Q) resulted in reduced protein levels compared to controls, suggesting a loss-of-function effect. Expression of the missense mutation was unable to rescue lethality in Ogdh-null Drosophila, also consistent with a loss of function. This patient had normal early development until about 8 years of age when he had onset of hearing loss, gait difficulties, scoliosis, and retinopathy. He later developed distal muscle weakness and hypotrophy, pyramidal signs, pes cavus, and progressive lower limb spasticity ultimately requiring a wheelchair. Other features included dysphagia, dysarthria, tremor, dysmetria, and sensorimotor neuropathy. He had normal cognition and no behavioral abnormalities.
For discussion of the c.1464T-C transition (c.1464T-C, NM_018245) in the OGDHL gene, resulting in a splicing defect, that was found in compound heterozygous state in a patient with Yoon-Bellen neurodevelopmental syndrome (YOBELN; 619701) by Yap et al. (2021), see 617513.0003.
In a 6-year-old boy (P6), born of consanguineous Pakistani parents, with Yoon-Bellen neurodevelopmental syndrome (YOBELN; 619701), Yap et al. (2021) identified a homozygous c.730C-T transition (c.730C-T, NM_018245) in the OGDHL gene, resulting in an arg244-to-trp (R244W) substitution at a conserved residue. The mutation, which was found by exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. It was present at a very low frequency (less than 9.6 x (10-5)) in the gnomAD database. Functional studies of patient cells were not performed, but transfection of the orthologous mutation in Drosophila (R261W) indicated that it caused decreased protein levels, suggesting a hypomorphic effect. Expression of the mutation was unable to rescue lethality in ogdh-null Drosophila, consistent with a loss of function. The boy was severely affected with inability to walk due to spastic quadriplegia, no visual interaction, roving eye movements, optic atrophy, and impaired intellect. He had global developmental delay from infancy and onset of multifocal clonic seizures at age 2 years. Although seizures were eventually controlled, the phenotype was consistent with a developmental and epileptic encephalopathy. Other features included microcephaly, scoliosis, high-arched palate, hip dysplasia, and swallowing difficulties. Brain imaging showed periventricular leukomalacia and thin corpus callosum.
In a 2.5-year-old boy (P8), born of consanguineous Iranian parents, with Yoon-Bellen neurodevelopmental syndrome (YOBELN; 619701), Yap et al. (2021) identified a homozygous c.895A-G transition (c.895A-G, NM_018245) in the OGDHL gene, resulting in an arg299-to-gly (R299G) substitution at a conserved residue. The mutation, which was found by exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. It was present at a low frequency (8.2 x 10(-6)) in the gnomAD database. Functional studies of patient cells were not performed, but expression of the orthologous Drosophila mutant (R316G) in Drosophila neurons resulted in reduced protein levels compared to controls, suggesting a loss-of-function effect. Expression of the mutation was unable to rescue lethality in ogdh-null Drosophila, also consistent with a loss of function. The patient presented in the first months of life with hypotonia, ptosis, nystagmus, unclear speech, and drooling, and later showed moderate developmental delay with severely impaired intellectual development.
Bunik, V. I., Degtyarev, D. Structure-function relationships in the 2-oxo acid dehydrogenase family: substrate-specific signatures and functional predictions for the 2-oxoglutarate dehydrogenase-like proteins. Proteins 71: 874-890, 2008. [PubMed: 18004749] [Full Text: https://doi.org/10.1002/prot.21766]
Nagase, T., Ishikawa, K., Kikuno, R., Hirosawa, M., Nomura, N., Ohara, O. Prediction of the coding sequences of unidentified human genes. XV. The complete sequences of 100 new cDNA clones from brain which code for large proteins in vitro. DNA Res. 6: 337-345, 1999. [PubMed: 10574462] [Full Text: https://doi.org/10.1093/dnares/6.5.337]
Sen, T., Sen, N., Noordhuis, M. G., Ravi, R., Wu, T.-C., Ha, P. K., Sidransky, D., Hoque, M. O. OGDHL is a modifier of AKT-dependent signaling and NF-kappaB function. PLoS One 7: e48770, 2012. Note: Electronic Article. [PubMed: 23152800] [Full Text: https://doi.org/10.1371/journal.pone.0048770]
Yap, Z. Y., Efthymiou, S., Seiffert, S., Vargas Parra, K., Lee, S., Nasca, A., Maroofian, R., Schrauwen, I., Pendziwiat, M., Jung, S., Bhoj, E., Striano, P., and 29 others. Bi-allelic variants in OGDHL cause a neurodevelopmental spectrum disease featuring epilepsy, hearing loss, visual impairment, and ataxia. Am. J. Hum. Genet. 108: 2368-2384, 2021. [PubMed: 34800363] [Full Text: https://doi.org/10.1016/j.ajhg.2021.11.003]
Yoon, W. H., Sandoval, H., Nagarkar-Jaiswal, S., Jaiswal, M., Yamamoto, S., Haelterman, N. A., Putluri, N., Putluri, V., Sreekumar, A., Tos, T., Aksoy, A., Donti, T., and 13 others. Loss of nardilysin, a mitochondrial co-chaperone for alpha-ketoglutarate dehydrogenase, promotes mTORC1 activation and neurodegeneration. Neuron 93: 115-131, 2017. [PubMed: 28017472] [Full Text: https://doi.org/10.1016/j.neuron.2016.11.038]