This report describes multisystemic disorder with developmental delay, skeletal, cardiac, and neurological abnormalities, TMEM208-related. The human gene implicated is TMEM208, which encodes a highly-conserved protein localized to the ER. There is one high-scoring fly ortholog, Dmel\Tmem208, for which multiple genetic reagents, including classical alleles, an amorphic allele, RNAi-targeting constructs, and alleles caused by insertional mutagenesis, have been generated.
Multiple UAS constructs of the human Hsap\TMEM208 gene, including wild-type and human disease-implicated variants, have been introduced into flies. See the 'Disease-Implicated Variants' table below. Heterologous rescue (functional complementation) has been observed for phenotypes of an amorphic allele of Dmel\Tmem208. Full rescue is observed for wild-type Hsap\TMEM208, while partial complementation is observed for variant constructs. Flies expressing a mild loss-of-function Hsap\TMEM208 in a Dmel\Tmem208 null background display an increase in bang-sensitivy when aged.
Amorphic alleles of Dmel\Tmem208 are semilethal, with ~10% adult escapers. Escapers exhibit a significantly reduced lifespan, bang-sensitivity, and morphological anomolies in eye and wing tissues consistant with planar cell polarity defects. Loss of Dmel\Tmem208 induces a mild but consistent ER stress response.
[updated Apr. 2024 by FlyBase; FBrf0222196]
A single individual with compound heterozygous variants in TMEM208 presented with global developmental delay and a multisystemic disorder, including gut malrotation, dysmorphic features including abnormal skeletal and ocular features, lymphopenia, heart defects, failure to thrive, perioral cyanosis with feeding, seizures, idiopathic intracranial hypertension with papilledema, hypoglycemia, idiopathic dilatation of the main pulmonary artery and aortic root, two posterior parietal hair whorls, frontal prominence, bilateral epicanthal folds, micrognathia, short neck, and a mild 5th finger clinodactyly. A number of these features are suggestive of planar cell polarity defects (Dutta, et al. 2024, pubmed:38381787; FBrf0258821).
This disorder is associated with biallelic loss of function variants of the gene TMEM208 (Dutta, et al. 2024, pubmed:38381787; FBrf0258821).
TMEM208 encodes a highly conserved protein which is localized in the endoplasmic reticulum (ER). The protein is linked to autophagy and ER stress. [provided by RefSeq, Dec 2015]
One to one (1 human to 1 Drosophila); TMEM208 has one high-scoring Drosophila ortholog, Tmem208.
High-scoring ortholog of human TMEM208 (1 Drosophila to 1 human).
