• Yoon-Bellen neurodevelopmental syndrome

Based on phenotypic findings in Drosophila and on experiments showing that the Drosophila orthologs of NRDC and OGDH/OGDHL interact, the BHCMG database was used to identify individuals carrying variants of OGDH or OGDHL. (See neurodegenerative disease, NRDC-related, FBhh0000718.) A missense mutation in the human OGDHL gene emerged as a top candidate for implication in a syndrome of severe developmental delay with cerebral and cerebellar atrophy and corpus callosum abnormality. Subsequently, additional cases have been identified; this disease exhibits autosomal recessive inheritance.

OGDHL is a paralog of OGDH, oxoglutarate dehydrogenase, a subunit of the 2-oxoglutarate dehydrogenase complex, which participates in the citric acid (TCA) cycle in the mitochondrial matrix. There are two Drosophila orthologs of OGDH and OGDHL, Ogdh and CG33791, for which RNAi targeting constructs and alleles caused by insertional mutagenesis have been generated. For Ogdh, there is also a loss-of-function allele created by insertion of a T24-GAL4 driver construct that also results in Ogdh-relevant stage- and tissue-specific expression of the driver.

Multiple UAS constructs of the human gene Hsap\OGDHL, have been introduced into flies, including wild-type and OGDHL variants implicated in this human disease. Partial heterologous rescue (functional complementation) has been demonstrated: for neurophysiology defective phenotypes of Dmel\Ogdh, rescue is observed when wild-type Hsap\OGDHL is co-expressed.

Multiple variants implicated in this disease have been assessed using transgenic constructs of the human gene and analogous mutations in fly gene; see the 'Disease-Implicated Variants' table, below. Variants have been assessed for ability to rescue the lethal and neurophysiology phenotypes of Dmel\Ogdh.

A severe loss-of-function mutation of Dmel\Ogdh causes lethality and neurophysiology defects. Using an eye-specific driver, RNAi directed against Ogdh results in age-progressive loss of synaptic transmission in photoreceptor cells. Physical interactions of Dmel\Ogdh have been described; see below and in the Ogdh gene report.

Work in Drosophila has contributed to the characterization of NRDC as a mitochondrial chaperone or co-chaperone for OGDH (see the human disease model report 'neurodegenerative disease, NRDC-related' FBhh0000718). See also the human disease model report 'oxoglutarate dehydrogenase deficiency' (FBhh0001423).

[updated Jan. 2022 by FlyBase; FBrf0222196]