In Silico Analysis of the L-2-Hydroxyglutarate Dehydrogenase Gene Mutations and Their Biological Impact on Disease Etiology

Abstract

The L-2-hydroxyglutarate dehydrogenase (L2HGDH) gene encodes an important mitochondrial enzyme. However, its altered activity results in excessive levels of L-2-hydroxyglutarate, which results in diverse psychiatric features of intellectual disability. In the current study, we executed an in-silico analysis of all reported L2HGDH missense and nonsense variants in order to investigate their biological significance. Among the superimposed 3D models, the highest similarity index for a wild-type structure was shown by the mutant Glu336Lys (87.26%), while the lowest similarity index value was shown by Arg70* (10.00%). Three large active site pockets were determined using protein active site prediction, in which the 2nd largest pocket was shown to encompass the substrate L-2-hydroxyglutarate (L2HG) binding residues, i.e., 89Gln, 195Tyr, 402Ala, 403Gly and 404Val. Moreover, interactions of wild-type and mutant L2HGDH variants with the close functional interactor D2HGDH protein resulted in alterations in the position, number and nature of networking residues. We observed that the binding of L2HG with the L2HGDH enzyme is affected by the nature of the amino acid substitution, as well as the number and nature of bonds between the substrate and protein molecule, which are able to affect its biological activity.

L-2 hydroxyglutaric aciduria: report of a Mexican-Mayan patient with the mutation c.569C>T and response to vitamin supplements and levocarnitine

“…L2HGA gene (14q22.1) encodes a putative mitochondrial protein with homology to flavin adenine dinucleotide (FAD) dependent oxidoreductases. So far, the human gene mutation database has reported 52 missense or nonsense mutations implicated in the reduced action of the L2HGDH enzyme [13][14][15]. The genetic variant detected in our patient is a missense mutation leading to a substitution of a threonine by a isoleucine in position 190 of the encoded protein (p.Thr190Ile) lying in the highly conserved FAD-binding domain, disturbing the enzymatic function.…”

Structure and biochemical characterization of l-2-hydroxyglutarate dehydrogenase and its role in the pathogenesis of l-2-hydroxyglutaric aciduria

“…Deficient activity of hs L2HGDH can lead to l -2-HG accumulation, which has been suggested to be the cause of l -2-HGA. So far, 36 missense mutations and 13 truncating mutations of hs L2HGDH have been identified in l -2-HGA patients ( 55 , 56 ). Truncating mutations usually lead to the absence or the loss of function of the protein and thus are classified as pathogenic.…”

“…This article contains supporting information ( 37 , 53 , 55 , 58 , 68 , 69 , 70 , 71 , 72 , 73 , 74 , 75 , 76 , 77 , 78 , 79 , 80 , 81 , 82 , 83 , 84 , 85 ).…”

Emerging Epidemiological Data on Rare Intellectual Disability Syndromes from Analyzing the Data of a Large Iranian Cohort

“…This gene provides L-2-hydroxyglutarate dehydrogenase, a mitochondrial enzyme involved in the conversion of L-2hydroxyglutarate to 2-ketoglutarate. 63 Studies in mice have shown that a defective form of L-2-hydroxyglutarate dehydrogenase leads to white matter abnormalities, neuroinflammation, improper neurogenesis of the hippocampal region, and neurodegeneration. 64 Mutations in this gene cause L-2-hydroxyglutaric aciduria, characterized by ID, cerebellar ataxia, epilepsy, speech problems, and an increased amount of L-2-hydroxyglutaric acid in urine, blood, and cerebrospinal fluid.…”

“…64 Mutations in this gene cause L-2-hydroxyglutaric aciduria, characterized by ID, cerebellar ataxia, epilepsy, speech problems, and an increased amount of L-2-hydroxyglutaric acid in urine, blood, and cerebrospinal fluid. 63 Lines Homolog 1; LINS1…”