This report describes Charcot-Marie-Tooth disease, dominant intermediate E (CMTDIE), also known as Charcot-Marie-Tooth neuropathy with focal segmental glomerulonephritis. CMTDIE exhibits autosomal dominant inheritance. The human gene implicated in this disease is INF2, a member of the formin family; the INF2 protein plays a role in polymerization and depolymerization of actin filaments and in regulation of cytoskeletal dynamics. INF2 is also implicated in a sub-type of focal segmental glomerulosclerosis (see FBhh0001284).
Multiple UAS constructs of the human Hsap\INF2 gene have been introduced into flies, including wild-type and variants implicated in disease; see the 'Disease-Implicated Variants' table, below. Phenotypes were assessed in the garland nephrocytes of third instar larvae; fly nephrocytes are functionally homologous to the podocytes of vertebrates. The distribution and organization of cytosolic and cortical actin in the nephrocytes was assessed, as well as the impact upon the structure of the slit diaphragms. Phenotypes of variants associated with focal segmental glomerulosclerosis (FSGS5, FBhh0001284) and this form of Charcot-Marie-Tooth disease (CMTDIE) have been compared.
The most closely related orthologous gene in Drosophila is form3, which is also orthologous to the human gene FHDC1. Animals homozygous for form3 loss-of-function alleles are lethal prior to the third instar larval stage. Using a GAL4 driver expressed in class IV dendritic arborization neurons, RNAi-mediated knockdown of form3 results in severe dendritic reductions and a rudimentary arbor with defects in distal higher order branching. Disruptions in F-actin
cytoskeletal distribution and a severe reduction of dendritic stable microtubules are observed.
[updated Sep. 2021 by FlyBase; FBrf0222196]
Charcot-Marie-Tooth disease (CMT) constitutes a clinically and genetically heterogeneous group of hereditary motor and sensory peripheral neuropathies. CMT is divided into several major types: Type 1 is characterized by demyelination and by a significantly slowed motor median nerve conduction velocity (NCV). Type 2 is characterized by axonal abnormalities and a normal or slightly reduced NCV. "Intermediate" types describe CMT families with nerve conduction velocities, in different affected individuals, that overlap the division between Type 1 and Type 2. Additional types are defined on the basis inheritance patterns. [from MIM:609260 and MIM:606482; 2015.12.15]
Symptoms typically include progressive distal muscle weakness and atrophy, often associated with mild to moderate sensory loss, depressed tendon reflexes, and high-arched feet. [from Gene Reviews, http://www.ncbi.nlm.nih.gov/books/NBK1358 2015.12.15]
[CHARCOT-MARIE-TOOTH DISEASE, DOMINANT INTERMEDIATE E; CMTDIE](https://omim.org/entry/614455)
[INVERTED FORMIN 2; INF2](https://omim.org/entry/610982)
Autosomal dominant intermediate Charcot-Marie-Tooth disease E with focal segmental glomerulonephritis is characterized by the neurologic features of CMT, including distal muscle weakness and atrophy and distal sensory loss, and the features of FSGS (focal segmental glomerulosclerosis), including proteinuria, progression to end-stage renal disease, and a characteristic histologic pattern on renal biopsy (summary by Boyer et al., 2011; pubmed:22187985). [from MIM:614455; 2020.11.07]
Dominant intermediate Charcot-Marie-Tooth disease E (CMTDIE) is caused by heterozygous mutation in the INF2 gene. [from MIM:614455; 2020.11.07]
Many to one: 2 human genes to 1 Drosophila gene; multiple similar genes in both species. The two human genes are INF2 and FHDC1.
Moderate-scoring ortholog of human INF2 and FHDC1 (1 Drosophila to 2 human). Dmel\form3 shares 26-28% identity and 40-44% similarity with the human genes.
