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FB2026_01
,
released March 12, 2026
This report describes Charcot-Marie-Tooth disease, INSC-related, a subtype of axonal Charcot-Marie-Tooth disease. The human gene implicated is INSC, which encodes INSC Spindle Orientation Adaptor Protein. There is one moderate-scoring fly ortholog, Dmel\insc, for which multiple genetic reagents, including loss of function alleles, RNAi-targeting constructs, and alleles caused by insertional mutagenesis have been generated.
Multiple UAS constructs of the human Hsap\INSC gene, including wild-type and a human disease-implicated variant, have been introduced into flies. See the 'Disease-Implicated Variants' table below.
Pan-neuronal RNAi-mediated knockdown of Dmel\insc results in progressive adult-onset locomotor deficits. Heterologous rescue of this phenotype by coexpression of wild-type Hsap\INSC has been demonstrated. Proprioceptor-specific RNAi-mediated knockdown of Dmel\insc results in locomotor impairment and gait changes.
[updated May 2024 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]
Eight members of a three generation family presented with autosomal dominant CMT2. All patients presented with slowly progressive distal sensory loss and gait unsteadiness with absent or mild weakness in the limbs with onset ranging from age 7 to 29 years. nerve conduction studies revealed axonal sensorimotor polyneuropathy with sensory predominant features (Yeh, et al., 2024, pubmed:38589651; FBrf0259513).
Charcot-Marie-Tooth disease, INSC-related exhibits an autosomal dominant inheritance pattern (Yeh, et al., 2024, pubmed:38589651; FBrf0259513).
INSC may function as an adapter linking the Par3 complex to the GPSM1/GPSM2 complex (Izaki, et al. 2006, pubmed:16458856). Involved in spindle orientation during mitosis. May regulate cell proliferation and differentiation in the developing nervous system. May play a role in the asymmetric division of fibroblasts and participate in the process of stratification of the squamous epithelium (By similarity). (UniProtKB/Swiss-Prot INSC_HUMAN,Q1MX18)
One to one (1 human to 1 Drosophila); INSC has one moderate-scoring Drosophila ortholog, insc.
Mderate scoring ortholog of human INSC (1 Drosophila to 1 human).