SEC31A mutation affects ER homeostasis, causing a neurological syndrome

Abstract

BackgroundConsanguineous kindred presented with an autosomal recessive syndrome of intrauterine growth retardation, marked developmental delay, spastic quadriplegia with profound contractures, pseudobulbar palsy with recurrent aspirations, epilepsy, dysmorphism, neurosensory deafness and optic nerve atrophy with no eye fixation. Affected individuals died by the age of 4. Brain MRI demonstrated microcephaly, semilobar holoprosencephaly and agenesis of corpus callosum. We aimed at elucidating the molecular basis of this disease.MethodsGenome-wide linkage analysis combined with whole exome sequencing were performed to identify disease-causing variants. Functional consequences were investigated in fruit flies null mutant for the Drosophila SEC31A orthologue. SEC31A knockout SH-SY5Y and HEK293T cell-lines were generated using CRISPR/Cas9 and studied through qRT-PCR, immunoblotting and viability assays.ResultsThrough genetic studies, we identified a disease-associated homozygous nonsense mutation in SEC31A. We demonstrate that SEC31A is ubiquitously expressed, and that the mutation triggers nonsense-mediated decay of its transcript, comprising a practical null mutation. Similar to the human disease phenotype, knockdown SEC31A flies had defective brains and early lethality. Moreover, in line with SEC31A encoding one of the two coating layers comprising the Coat protein complex II (COP-II) complex, trafficking newly synthesised proteins from the endoplasmic reticulum (ER) to the Golgi, CRISPR/Cas9-mediated SEC31A null mutant cells demonstrated reduced viability through upregulation of ER-stress pathways.ConclusionWe demonstrate through human and Drosophila genetic and in vitro molecular studies, that a severe neurological syndrome is caused by a null mutation in SEC31A, reducing cell viability through enhanced ER-stress response, in line with SEC31A’s role in the COP-II complex.

Loss of SMPD4 Causes a Developmental Disorder Characterized by Microcephaly and Congenital Arthrogryposis

“…The presentation of the SMPD4 variant phenotype with microcephaly, simplified gyral pattern, and congenital contractures is reminiscent of cerebro-oculo-facio-skeletal syndrome (COFS [MIM: 609413/ 216400]), a syndrome with congenital microcephaly caused by DNA repair defects (Table S7) or the recently described SEC31A (MIM: 610257) variant syndrome. 19,25 COFS was in fact the first suspected diagnosis in many of our case subjects, but the absence of cataract is unusual for COFS and DNA repair tests in cultured fibroblasts from affected individuals have repeatedly shown to be normal (G.M.S.M. and F.W.V., unpublished data).…”

“…ER stress, induced by genetic alterations or virus infections, has previously been implicated in microcephaly pathogenesis. [25][26][27] In mouse embryonic stem cells, ER stress promotes accelerated neuronal differentiation of the pluripotent and glial progenitor pools which can lead to microcephaly and global hypomyelination, both features observed in the affected children in our cohort. 28,29 Cells with ER perturbations usually activate concomitant signaling pathways, including the most studied UPR, to restore homeostasis.…”

Phenotypic variability and mutation hotspot in COX15‐related Leigh syndrome

“…Genome‐wide linkage analysis of all family members (Patients I:1,2, II:1–5) and WES of both affected siblings (Patients II:3,4) was performed as previously described (Halperin et al, 2019). WES data were analyzed through using QIAGEN's Ingenuity® Variant Analysis™ software (http://www.qiagenbioinformatics.com/ingenuity-variant-analysis; QIAGEN, Redwood City, CA), excluding variants observed with an allele frequency ≥1% in the 1,000 Genomes Project (http://www.internationalgenome.org/) or variants appearing in a homozygous state in our in‐house WES database of 300 controls.…”

ER-to-Golgi Trafficking and Its Implication in Neurological Diseases

“…Mutations in the genes encoding or directly affecting the function of essential components of the COPII machinery are linked to various neurological diseases. For example, a mutation in SEC31A that leads to nonsense-mediated decay of its transcript is linked to a recessive neurological syndrome characterized by intrauterine growth retardation, marked developmental delay, and epilepsy [80]. Loss of function of Sec31 in flies also results in severely defective brain development and early lethality [80].…”

“…For example, a mutation in SEC31A that leads to nonsense-mediated decay of its transcript is linked to a recessive neurological syndrome characterized by intrauterine growth retardation, marked developmental delay, and epilepsy [80]. Loss of function of Sec31 in flies also results in severely defective brain development and early lethality [80]. Loss-of-function mutations in SEC24B in humans are associated with neural tube defects [81].…”