Biallelic EPB41L3 variants underlie a developmental disorder with seizures and myelination defects.
Document Type
Article
Publication Date
12-3-2024
Original Citation
Werren E,
Rodriguez Bey G,
Majethia P,
Kaur P,
Patil S,
Kekatpure M,
Afenjar A,
Qebibo L,
Burglen L,
Tomoum H,
Demurger F,
Duborg C,
Siddiqui S,
Tsan Y,
Abdullah U,
Ali Z,
Saadi S,
Baig S,
Houlden H,
Maroofian R,
Padiath Q,
Bielas S,
Shukla A.
Biallelic EPB41L3 variants underlie a developmental disorder with seizures and myelination defects. Brain. 2024;147(12):4033–42
Keywords
JGM, Humans, Male, Animals, Female, Mice, Seizures, Developmental Disabilities, Child, Child, Preschool, Myelin Sheath, Pedigree, Adolescent, Oligodendroglia, Membrane Proteins, Exome Sequencing
JAX Source
Brain. 2024;147(12):4033–42
ISSN
1460-2156
PMID
39292993
DOI
https://doi.org/10.1093/brain/awae299
Abstract
Erythrocyte membrane protein band 4.1 like 3 (EPB41L3: NM_012307.5), also known as DAL1, encodes the ubiquitously expressed, neuronally enriched 4.1B protein, part of the 4.1 superfamily of membrane-cytoskeleton adaptors. The 4.1B protein plays key roles in cell spreading, migration and cytoskeletal scaffolding that support oligodendrocyte axon adhesions essential for proper myelination. We herein describe six individuals from five unrelated families with global developmental delay, intellectual disability, seizures, hypotonia, neuroregression and delayed myelination. Exome sequencing identified biallelic variants in EPB41L3 in all affected individuals: two nonsense [c.466C>T, p.(R156*); c.2776C>T, p.(R926*)] and three frameshift [c.666delT, p.(F222Lfs*46); c.2289dupC, p.(V764Rfs*19); c.948_949delTG, p.(A317Kfs*33)]. Quantitative-real time PCR and western blot analyses of human fibroblasts harbouring EPB41L3:c.666delT, p.(F222Lfs*46) indicated ablation of EPB41L3 mRNA and 4.1B protein expression. Inhibition of the nonsense mediated decay (NMD) pathway led to an upregulation of EPB41L3:c.666delT transcripts, supporting NMD as a pathogenic mechanism. Epb41l3-deficient mouse oligodendroglia cells showed significant reduction in mRNA expression of key myelin genes, reduced branching and increased apoptosis. Our report provides the first clinical description of an autosomal recessive disorder associated with variants in EPB41L3, which we refer to as EPB41L3-associated developmental disorder (EADD). Moreover, our functional studies substantiate the pathogenicity of EPB41L3 hypothesized loss-of-function variants.