@article {924, title = {Mutations in Spliceosomal Genes PPIL1 and PRP17 Cause Neurodegenerative Pontocerebellar Hypoplasia with Microcephaly.}, journal = {Neuron}, volume = {109}, year = {2021}, month = {2021 01 20}, pages = {241-256.e9}, abstract = {

Autosomal-recessive cerebellar hypoplasia and ataxia constitute a group of heterogeneous brain disorders caused by disruption of several fundamental cellular processes. Here, we identified 10 families showing a neurodegenerative condition involving pontocerebellar hypoplasia with microcephaly (PCHM). Patients harbored biallelic mutations in genes encoding the spliceosome components Peptidyl-Prolyl Isomerase Like-1 (PPIL1) or Pre-RNA Processing-17 (PRP17). Mouse knockouts of either gene were lethal in early embryogenesis, whereas PPIL1 patient mutation knockin mice showed neuron-specific apoptosis. Loss of either protein affected splicing integrity, predominantly affecting short and high GC-content introns and genes involved in brain disorders. PPIL1 and PRP17 form an active isomerase-substrate interaction, but we found that isomerase activity is not critical for function. Thus, we establish disrupted splicing integrity and "major spliceosome-opathies" as a new mechanism underlying PCHM and neurodegeneration and uncover a non-enzymatic function of a spliceosomal proline isomerase.

}, keywords = {Amino Acid Sequence, Animals, Cell Cycle Proteins, Cerebellar Diseases, Cohort Studies, Female, Gene Knockout Techniques, HEK293 Cells, Heredodegenerative Disorders, Nervous System, Humans, Male, Mice, Mice, Inbred C57BL, Mice, Transgenic, Microcephaly, Mutation, Pedigree, Peptidylprolyl Isomerase, Protein Structure, Secondary, Protein Structure, Tertiary, RNA Splicing Factors, Spliceosomes}, issn = {1097-4199}, doi = {10.1016/j.neuron.2020.10.035}, author = {Chai, Guoliang and Webb, Alice and Li, Chen and Antaki, Danny and Lee, Sangmoon and Breuss, Martin W and Lang, Nhi and Stanley, Valentina and Anzenberg, Paula and Yang, Xiaoxu and Marshall, Trevor and Gaffney, Patrick and Wierenga, Klaas J and Chung, Brian Hon-Yin and Tsang, Mandy Ho-Yin and Pais, Lynn S and Lovgren, Alysia Kern and VanNoy, Grace E and Rehm, Heidi L and Mirzaa, Ghayda and Leon, Eyby and Diaz, Jullianne and Neumann, Alexander and Kalverda, Arnout P and Manfield, Iain W and Parry, David A and Logan, Clare V and Johnson, Colin A and Bonthron, David T and Valleley, Elizabeth M A and Issa, Mahmoud Y and Abdel-Ghafar, Sherif F and Abdel-Hamid, Mohamed S and Jennings, Patricia and Zaki, MAH S and Sheridan, Eamonn and Gleeson, Joseph G} } @article {488, title = {Mutations in LNPK, Encoding the Endoplasmic Reticulum Junction Stabilizer Lunapark, Cause a Recessive Neurodevelopmental Syndrome.}, journal = {Am J Hum Genet}, volume = {103}, year = {2018}, month = {2018 08 02}, pages = {296-304}, 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.

}, issn = {1537-6605}, doi = {10.1016/j.ajhg.2018.06.011}, author = {Breuss, Martin W and Nguyen, An and Song, Qiong and Nguyen, Thai and Stanley, Valentina and James, Kiely N and Musaev, Damir and Chai, Guoliang and Wirth, Sara A and Anzenberg, Paula and George, Renee D and Johansen, Anide and Ali, Shaila and Zia-Ur-Rehman, Muhammad and Sultan, Tipu and Zaki, Maha S and Gleeson, Joseph G} } @article {493, title = {Mutations in GPAA1, Encoding a GPI Transamidase Complex Protein, Cause Developmental Delay, Epilepsy, Cerebellar Atrophy, and Osteopenia.}, journal = {Am J Hum Genet}, volume = {101}, year = {2017}, month = {2017 Nov 02}, pages = {856-865}, abstract = {

Approximately one in every 200 mammalian proteins is anchored to the cell membrane through a glycosylphosphatidylinositol (GPI) anchor. These proteins play important roles notably in neurological development and function. To date, more than 20 genes have been implicated in the biogenesis of GPI-anchored proteins. GPAA1 (glycosylphosphatidylinositol anchor attachment 1) is an essential component of the transamidase complex along with PIGK, PIGS, PIGT, and PIGU (phosphatidylinositol-glycan biosynthesis classes K, S, T, and U, respectively). This complex orchestrates the attachment of the GPI anchor to the C terminus of precursor proteins in the endoplasmic reticulum. Here, we report bi-allelic mutations in GPAA1 in ten individuals from five families. Using whole-exome sequencing, we identified two frameshift mutations (c.981_993del [p.Gln327Hisfs102] and c.920delG [p.Gly307Alafs11]), one intronic splicing mutation (c.1164+5C>T), and six missense mutations (c.152C>T [p.Ser51Leu], c.160_161delinsAA [p.Ala54Asn], c.527G>C [p.Trp176Ser], c.869T>C [p.Leu290Pro], c.872T>C [p.Leu291Pro], and c.1165G>C [p.Ala389Pro]). Most individuals presented with global developmental delay, hypotonia, early-onset seizures, cerebellar atrophy, and osteopenia. The splicing mutation was found to decrease GPAA1 mRNA. Moreover, flow-cytometry analysis of five available individual samples showed that several GPI-anchored proteins had decreased cell-surface abundance in leukocytes (FLAER, CD16, and CD59) or fibroblasts (CD73 and CD109). Transduction of fibroblasts with a lentivirus encoding the wild-type protein partially rescued the deficiency of GPI-anchored proteins. These findings highlight the role of the transamidase complex in the development and function of the cerebellum and the skeletal system.

}, keywords = {Acyltransferases, Adolescent, Adult, Alleles, Atrophy, Bone Diseases, Metabolic, Cerebellum, Child, Child, Preschool, Developmental Disabilities, Epilepsy, Exome, Female, Fibroblasts, Glycosylphosphatidylinositols, Humans, Male, Membrane Glycoproteins, Muscle Hypotonia, Mutation, Pedigree, RNA, Messenger, Seizures}, issn = {1537-6605}, doi = {10.1016/j.ajhg.2017.09.020}, author = {Nguyen, Thi Tuyet Mai and Murakami, Yoshiko and Sheridan, Eamonn and Ehresmann, Sophie and Rousseau, Justine and St-Denis, Anik and Chai, Guoliang and Ajeawung, Norbert F and Fairbrother, Laura and Reimschisel, Tyler and Bateman, Alexandra and Berry-Kravis, Elizabeth and Xia, Fan and Tardif, Jessica and Parry, David A and Logan, Clare V and Diggle, Christine and Bennett, Christopher P and Hattingh, Louise and Rosenfeld, Jill A and Perry, Michael Scott and Parker, Michael J and Le Deist, Fran{\c c}oise and Zaki, Maha S and Ignatius, Erika and Isohanni, Pirjo and L{\"o}nnqvist, Tuula and Carroll, Christopher J and Johnson, Colin A and Gleeson, Joseph G and Kinoshita, Taroh and Campeau, Philippe M} }