This report describes neuropathy, hereditary motor and sensory, type VIB, which shows autosomal recessive inheritance. This type of neuropathy was previously known as Charcot-Marie-Tooth disease, type 6B. The human gene implicated in this disease is SLC25A46, a mitochondrial solute carrier transport protein. There are two high-ranking orthologs of SLC25A46 in Drosophila, Slc25A46a and Slc25A46b. Alleles carrying RNAi targeting constructs have been generated for both genes.
The human gene SLC25A46 has not been introduced into flies.
Knocking down Slc25A46b in neurons (elav-GAL4 driver) results in a reduction in larval and adult locomotion (crawling/climbing assays), as well as an increase in markers of mitochondrial stress. In the eye, Slc25A46b knockdown causes aberrant projections from photoreceptors R7-R8 and shortened optic stalks. At neuromuscular junctions (NMJs), Slc25A46b knockdown flies have reduced branch length, fewer and smaller 1b boutons, and smaller, less dense active zones. Mitochondria in Slc25A46b knockdown NMJs are larger and more dense, although not more numerous. Knockdown of the histone deacetylase HDAC1 can rescue several neuron-specific Slc25A46b RNAi phenotypes, suggesting that HDAC1 is a negative regulator of Slc25A46b.
Subsequently, depletion of the second Drosophila ortholog, Slc25A46a, was assessed; similar phenotypes were observed. Pan-neuronal knockdown of Slc25A46a effected by RNAi leads to mitochondrial defects and an aberrant synaptic morphology, resulting in locomotive defects and learning disability.
FlyBase note: both Suda et al. 2018 (FBrf0238690) and Suda et al. 2019 (FBrf0244100) refer to a single SLC25A46 ortholog in Drosophila, CG5755, which is currently known as Slc25A46b. Human SLC25A46 is orthologous to two Drosophila paralogs, Slc25A46a and Slc25A46b. Both papers use RNAi lines and qPCR primers targeting Slc25A46b, and a custom-generated antibody against Cys-NKSSTTKSPSISSI-OH, which targets a sequence present only in Slc25A46b. Expression data from modENCODE and FlyAtlas (http://flyatlas.org/atlas.cgi?name=CG5755-RA) indicate that Slc25A46b expresses primarily in the testis, whereas its paralog Slc25A46a is expressed in a wider variety of tissues. Given the strong phenotypes seen by knocking Slc25A46b down in neurons in FBrf0238690, it is possible that there is more expression of Slc25A46b in neurons than was observed in the modENCODE RNA-seq and FlyAtlas data, and/or that there is sufficient similarity between the sequences of Slc25A46a and Slc25A46b to allow for cross-reactivity of RNAi constructs.
[updated Nov. 2020 by FlyBase; FBrf0222196]
[NEUROPATHY, HEREDITARY MOTOR AND SENSORY, TYPE VIB, WITH OPTIC ATROPHY; HMSN6B](https://omim.org/entry/616505)
[SOLUTE CARRIER FAMILY 25, MEMBER 46; SLC25A46](https://omim.org/entry/610826)
Recessive SLC25A46 mutations cause a syndromic spectrum, including optic atrophy, cerebellar atrophy, and axonal neuropathy (MIM:616505). Specific presentations range from optic atrophy - plus disorder on the mild end of the spectrum to lethal Leigh syndrome and ponto-cerebellar hypoplasia in extreme cases. (Adapted from Abrams et al. 2018 and references therein, pubmed:30178502.)
Hereditary motor and sensory neuropathy type VIB is an autosomal recessive complex progressive neurologic disorder characterized mainly by early-onset optic atrophy resulting in progressive visual loss and peripheral axonal sensorimotor neuropathy with highly variable age at onset and severity. Affected individuals also have cerebellar or pontocerebellar atrophy on brain imaging, and they may show abnormal movements, such as ataxia, dysmetria, and myoclonus. The most severely affected patients are hypotonic at birth and die in infancy. Summary by Abrams et al. 2015 (pubmed:26168012) and Wan et al. 2016 (pubmed:27543974). [from MIM:616505, 2020.01.22]
Hereditary motor and sensory neuropathy type VIB with optic atrophy (HMSN6B) is caused by homozygous or compound heterozygous mutation in the SLC25A46 gene (MIM:610826) on chromosome 5q22. The transmission pattern of HMSN6B in the families reported by Abrams et al. 2015 (pubmed:26168012) was consistent with autosomal recessive inheritance. [from MIM:616505, 2020.01.22]
Dominant or recessive mutations in the SLC25A46 gene are associated with cerebellar and brainstem atrophy, peripheral neuropathy, global developmental delay, and optic atrophy in patients. This disorder spectrum has been defined as hereditary motor sensory neuropathy Type VIB (HMSN6B) and may be classified as Charcot-Marie-Tooth disease (CMT) type 2 in the Online Mendelian Inheritance in Man (MIM:616505), optic atrophy, and Leigh syndrome. This wide spectrum of disorders may be associated with the dysregulation of some epigenetic regulators. (Suda et al. 2019, FBrf0244100.)
Although the precise function of SLC25A46 is currently unknown, it is possible that it facilitates transport across the mitochondrial membrane or functions as a molecular adaptor protein similar to Ugo1 in yeast. In support of the adaptor hypothesis, SLC25A46 has been shown to molecularly interact with both OPA1 and MFN2, indicating that it could play a direct role in mitochondrial fusion/fission dynamics through these interactions. Additionally, SLC25A46 forms a complex with the cristae remodeling protein MIC60 also known as IMMT/Mitofilin and abnormal cristae and alterations in fusion/fission dynamics have been observed in several models. (Adapted from Abrams et al. 2018 and references therein, pubmed:30178502.)
One to many: 1 human gene to many Drosophila genes.
High-scoring ortholog of human SLC25A46, paralogous to Slc25A46a.
High-scoring ortholog of human SLC25A46, paralogous to Slc25A46b.
