Mutations in Spliceosomal Genes PPIL1 and PRP17 Cause Neurodegenerative Pontocerebellar Hypoplasia with Microcephaly.

Journal: 
Neuron
Publication Year: 
2020
Authors: 
Guoliang Chai
Alice Webb
Chen Li
Danny Antaki
Sangmoon Lee
Martin W Breuss
Nhi Lang
Valentina Stanley
Paula Anzenberg
Xiaoxu Yang
Trevor Marshall
Patrick Gaffney
Klaas J Wierenga
Brian Hon-Yin Chung
Mandy Ho-Yin Tsang
Lynn S Pais
Alysia Kern Lovgren
Grace E VanNoy
Heidi L Rehm
Ghayda Mirzaa
Eyby Leon
Jullianne Diaz
Alexander Neumann
Arnout P Kalverda
Iain W Manfield
David A Parry
Clare V Logan
Colin A Johnson
David T Bonthron
Elizabeth M A Valleley
Mahmoud Y Issa
Sherif F Abdel-Ghafar
Mohamed S Abdel-Hamid
Patricia Jennings
Maha S Zaki
Eamonn Sheridan
Joseph G Gleeson
PubMed link: 
33220177
Public Summary: 
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.
Scientific 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.