Mutations in LNPK, Encoding the Endoplasmic Reticulum Junction Stabilizer Lunapark, Cause a Recessive Neurodevelopmental Syndrome

Abstract

The dynamic shape of the endoplasmic reticulum (ER) is a reflection of its wide variety of critical cell biological functions. Consequently, perturbation of ER-shaping proteins can cause a range of human phenotypes. Here, we describe three affected children (from two consanguineous families) who carry homozygous loss-of-function mutations in LNPK (previously known as KIAA1715); this gene encodes lunapark, which is proposed to serve as a curvature-stabilizing protein within tubular three-way junctions of the ER. All individuals presented with severe psychomotor delay, intellectual disability, hypotonia, epilepsy, and corpus callosum hypoplasia, and two of three showed mild cerebellar hypoplasia and atrophy. Consistent with a proposed role in neurodevelopmental disease, LNPK was expressed during brain development in humans and mice and was present in neurite-like processes in differentiating human neural progenitor cells. Affected cells showed the absence of full-length lunapark, aberrant ER structures, and increased luminal mass density. Together, our results implicate the ER junction stabilizer lunapark in establishing the corpus callosum.

Ubiquitylation of the ER-Shaping Protein Lunapark via the CRL3KLHL12 Ubiquitin Ligase Complex

“…Although Lunapark is ubiquitously expressed, it is present at high levels in the CNS of mice and chickens during embryo development and is involved in synaptic vesicle transport in C. elegans neuronal structures (Ghila and Gomez, 2008). Furthermore, Lunapark expression was observed throughout brain development in both mice and humans as well as in differentiating neural precursor cells (Breuss et al, 2018). Recently, homozygous mutations in the gene encoding Lunapark have been described in three children with a recessive neurodevelopmental syndrome characterized by intellectual disability, psychomotor developmental delay, defects in social interactions, hyperactivity, inattention, and epilepsy (Breuss et al, 2018).…”

“…Furthermore, Lunapark expression was observed throughout brain development in both mice and humans as well as in differentiating neural precursor cells (Breuss et al, 2018). Recently, homozygous mutations in the gene encoding Lunapark have been described in three children with a recessive neurodevelopmental syndrome characterized by intellectual disability, psychomotor developmental delay, defects in social interactions, hyperactivity, inattention, and epilepsy (Breuss et al, 2018). Interestingly, hyperactivation of mTORC1 signaling observed in tuberous sclerosis complex patients results in epilepsy, neurodevelopmental delays, behavioral problems including attention deficit hyperactivity disorder, and autism spectrum disorder (Luarte et al, 2018;Switon et al, 2017).…”

Expression-based decision tree model reveals distinct microRNA expression pattern in pediatric neuronal and mixed neuronal-glial tumors

“…Performed here computational in silico analysis of miRNA-mRNA network also showed connection with genes expressed during human brain development, LNPK and ZBTB20 . Two out of 8 selected miRNAs have shown to target LNPK , encoding the endoplasmic reticulum junction stabilizer lunapark, gene with assigned role in neurodevelopmental disorders and plausible contribution to the epilepsy [35]. In turn transcriptional repressor ZBTB20 had confirmed function in neural precursor cells [36].…”

Recurrent homozygous damaging mutation in TMX2, encoding a protein disulfide isomerase, in four families with microlissencephaly

“…Partial or complete loss of TMX2 may thus predispose to cell death. While we have not linked the phenotypes from our cases to a molecular function in this study, increased ER stress during neurodevelopment has been linked to aberrant neuronal maturation and the subsequent development of neurodevelopmental disorders caused by abnormal neuronal differentiation and maturation 34 35. We hypothesise that loss of TMX2 in humans may lead to cell death-mediated depletion of neural progenitor cells in the developing cerebral cortex during embryogenesis, producing microlissencephaly.…”