This report describes lissencephaly 8 (LIS8), which is a subtype of lissencephaly; LIS8 exhibits autosomal recessive inheritance. The human gene implicated in this disease is TMTC3 (Transmembrane And Tetratricopeptide Repeat Containing 3); TMTC3 encodes a protein involved in the positive regulation of proteasomal protein degradation in the endoplasmic reticulum (ER), and the control of ER stress response. There is a single fly ortholog, Dmel\Tmtc3, for which RNAi targeting constructs and alleles caused by insertional mutagenesis have been generated.
A UAS construct of the wild-type human Hsap\TMTC3 gene has been introduced into flies; heterologous rescue (functional complementation) has been demonstrated.
Dmel\Tmtc3 has not been extensively characterized. Reduced function effected by pan-neuronal expression of an RNAi construct targeted to Dmel\Tmtc3 results in semi-lethality; surviving adults exhibit bang sensitivity (seizure-like behavior in response to mechanical disturbance).
[updated Apr. 2018 by FlyBase; FBrf0222196]
Lissencephaly represents a term for a spectrum of severe and rare brain malformations that result in a significant simplification (pachygyria) or even total absence (agyria) of brain convolutions. Based on the physical structure of the brain, lissencephaly can be generally divided into two distinct pathological forms: type I or classical lissencephaly, and type II or cobblestone lissencephaly (http://www.news-medical.net/health/Lissencephaly-Types.aspx; 2017.07.16).
[LISSENCEPHALY 8; LIS8](https://omim.org/entry/617255)
[TRANSMEMBRANE AND TETRATRICOPEPTIDE REPEAT DOMAINS-CONTAINING PROTEIN 3; TMTC3](https://omim.org/entry/617218)
Lissencephaly and periventricular nodular heterotopia (PVNH) are both neuronal migration disorders. PVNH represents a more focal disturbance in which neurons fail to migrate appropriately from the ventricular zone to the cortex; lissencephaly represents a more diffuse and extensive disturbance of neuronal migration. (Lee, 2017; Practical Pediatric Imaging)
Lissencephaly-8 is an autosomal recessive neurologic disorder characterized by delayed psychomotor development, intellectual disability with poor or absent speech, early-onset refractory seizures, and hypotonia. Brain imaging shows variable features, including cortical gyral abnormalities and hypoplasia of the corpus callosum, brainstem, and cerebellum (summary by Jerber et al., 2016; pubmed:27773428). [from MIM:617255; 2018.04.25]
Lissencephaly-8 (LIS8) is caused by homozygous or compound heterozygous mutation in the TMTC3 gene. [from MIM:617255; 2018.04.25]
TMTC3 encodes a protein involved in the positive regulation of proteasomal protein degradation in the endoplasmic reticulum (ER), and the control of ER stress response.
The TMTC3 transmembrane protein contains 10 tetratricopeptide repeats and is highly conserved; it is a positive regulator of the endoplasmic reticulum (ER) stress response (Racape et al., 2011; pubmed:21603654). [from MIM:617218; 2018.0.25]
One to one: 1 human to 1 Drosophila.
High-scoring ortholog of human TMTC3 (1 Drosophila to 1 human). Dmel\Tmtc3 shares 52% identity and 66% similarity with the human gene.
