2. Academic Validation
  3. Mutations in LNPK, Encoding the Endoplasmic Reticulum Junction Stabilizer Lunapark, Cause a Recessive Neurodevelopmental Syndrome

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

  • Am J Hum Genet. 2018 Aug 2;103(2):296-304. doi: 10.1016/j.ajhg.2018.06.011.
Martin W Breuss 1,  An Nguyen 1,  Qiong Song 1,  Thai Nguyen 1,  Valentina Stanley 1,  Kiely N James 1,  Damir Musaev 1,  Guoliang Chai 1,  Sara A Wirth 1,  Paula Anzenberg 1,  Renee D George 1,  Anide Johansen 1,  Shaila Ali 2,  Muhammad Zia-Ur-Rehman 2,  Tipu Sultan 2,  Maha S Zaki 3,  Joseph G Gleeson 4
Affiliations

Affiliations

  • 1 Department of Neurosciences, Howard Hughes Medical Institute, University of California, San Diego, La Jolla, CA 92093, USA; Rady Children's Institute for Genomic Medicine, San Diego, CA 92025, USA.
  • 2 Department of Pediatric Neurology, Children's Hospital and Institute of Child Health, Lahore 54000, Pakistan.
  • 3 Clinical Genetics Department, Human Genetics and Genome Research Division, National Research Centre, Cairo 12311, Egypt.
  • 4 Department of Neurosciences, Howard Hughes Medical Institute, University of California, San Diego, La Jolla, CA 92093, USA; Rady Children's Institute for Genomic Medicine, San Diego, CA 92025, USA. Electronic address: [email protected].
PMID: 30032983 DOI: 10.1016/j.ajhg.2018.06.011
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.

Keywords

KIAA1715; corpus callosum hypoplasia; endoplasmic reticulum; epilepsy; human genetics; hypotonia; lunapark; organelle morphology; recessive disease.

Figures