This report describes neurodevelopmental disorder with hypotonia, speech delay, and dysmorphic facies (NEDHSF), originally described as a syndromic form of intellectual disability; NEDHSF exhibits autosomal dominant inheritance. The human gene implicated in this disease is CERT1; CERT1 encodes a ceramide transporter that regulates intracellular trafficking of ceramides, which subsequently impacts levels of sphingolipid biosynthesis. There is a single orthologous gene in Drosophila, cert, for which multiple genetic reagents have been generated, including loss-of-function mutations, RNAi-targeting constructs, alleles caused by insertional mutagenesis, and overexpression constructs.
The human CERT1 has not been introduced into flies.
Experiments in Drosophila have been used to test the hypothesis that the phenotypes associated with this disease are due to CERT1 gain of function, caused by disruption of CERT1 autoregulation. Two genotypes have been used: one with multiple extra copies of wild-type Dmel\cert and one using a mutation in the fly gene analogous to a common and severe disease-implicated variant. (See the 'Disease-Implicated Variants' table below.) Both genotypes result in head and brain size defects and impaired locomotor activity; these phenotypes were ameliorated by pharmacological inhibition of CERT.
[updated Mar. 2025 by FlyBase; FBrf0222196]
Intellectual disability is characterized by impairments in intellectual functioning and adaptive behavior; symptoms must be present before a child becomes 18 years old (http://medical-dictionary.thefreedictionary.com/mental+retardation; 2016.01.19).
Intellectual disability can be subdivided into syndromic forms, characterized by cognitive impairment accompanied by dysmorphic features, malformations or neurological abnormalities, and nonsyndromic forms, characterized by cognitive impairment without additional features (Basel-Vanagaite, 2008; DOI: 10.1002/9780470015902.a0021454).
[NEURODEVELOPMENTAL DISORDER WITH HYPOTONIA, SPEECH DELAY, AND DYSMORPHIC FACIES; NEDHSF](https://omim.org/entry/616351)
[CERAMIDE TRANSPORTER 1; CERT1](https://omim.org/entry/604677)
Patients have a syndromic presentation characterized by infantile hypotonia, mild dysmorphologies, variable degrees of intellectual disability and motor and speech delays, increased pain tolerance, and seizures (Gehin, et al., pubmed:36976648; FBrf0256486).
Autosomal dominant intellectual developmental disorder 34 (MRD34) is caused by heterozygous mutation in the CERT1 (COL4A3BP) gene. [from MIM:616351; 2023.07.17]
CERT1 encodes a protein that mediates the intracellular trafficking of ceramides and diacylglycerol lipids in a non-vesicular manner. [GeneCards, CERT1; 2023.07.17]
A key checkpoint in sphingolipid biosynthesis occurs at contact sites between the endoplasmic reticulum and the trans Golgi membrane, where the ceramide transporter (CERT) transfers ceramide (Cer) from the ER to the trans Golgi for its conversion to sphingomyelin; when sufficient rates of SM production are reached, CERT is phosphorylated and undergoes a conformational change that renders it inactive (Gehin, et al., pubmed:36976648; FBrf0256486; and references cited therein)
One to one: 1 human gene to 1 Drosophila gene.
High-scoring ortholog of human CERT1 (1 Drosophila to 1 human).
