학술논문
Mutations in Spliceosomal Genes PPIL1 and PRP17 Cause Neurodegenerative Pontocerebellar Hypoplasia with Microcephaly
Document Type
article
Author
Chai, Guoliang; Webb, Alice; Li, Chen; Antaki, Danny; Lee, Sangmoon; Breuss, Martin W; Lang, Nhi; Stanley, Valentina; Anzenberg, Paula; Yang, Xiaoxu; Marshall, Trevor; Gaffney, Patrick; Wierenga, Klaas J; Chung, Brian Hon-Yin; Tsang, Mandy Ho-Yin; Pais, Lynn S; Lovgren, Alysia Kern; VanNoy, Grace E; Rehm, Heidi L; Mirzaa, Ghayda; Leon, Eyby; Diaz, Jullianne; Neumann, Alexander; Kalverda, Arnout P; Manfield, Iain W; Parry, David A; Logan, Clare V; Johnson, Colin A; Bonthron, David T; Valleley, Elizabeth MA; Issa, Mahmoud Y; Abdel-Ghafar, Sherif F; Abdel-Hamid, Mohamed S; Jennings, Patricia; Zaki, Maha S; Sheridan, Eamonn; Gleeson, Joseph G
Source
Neuron. 109(2)
Subject
Language
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.