TY - JOUR
T1 - Recessive PRDM13 mutations cause fatal perinatal brainstem dysfunction with cerebellar hypoplasia and disrupt Purkinje cell differentiation
AU - Coolen, Marion
AU - Altin, Nami
AU - Rajamani, Karthyayani
AU - Pereira, Eva
AU - Siquier-Pernet, Karine
AU - Puig Lombardi, Emilia
AU - Moreno, Nadjeda
AU - Barcia, Giulia
AU - Yvert, Marianne
AU - Laquerrière, Annie
AU - Pouliet, Aurore
AU - Nitschké, Patrick
AU - Boddaert, Nathalie
AU - Rausell, Antonio
AU - Razavi, Féréchté
AU - Afenjar, Alexandra
AU - Billette de Villemeur, Thierry
AU - Al-Maawali, Almundher
AU - Al-Thihli, Khalid
AU - Baptista, Julia
AU - Beleza-Meireles, Ana
AU - Garel, Catherine
AU - Legendre, Marine
AU - Gelot, Antoinette
AU - Burglen, Lydie
AU - Moutton, Sébastien
AU - Cantagrel, Vincent
N1 - Funding Information:
The project is funded by the Agence Nationale de la Recherche ANR-16-CE12- 0005-01, the Fondation pour la Recherche Médicale FRM-DEQ20160334938, and the patient association CSC “Connaître les syndromes Cérébelleux.” This work was also supported by state funding from the Agence Nationale de la Recherche under “Investissements d'avenir” program (ANR-10-IAHU-01), the Fondation Bettencourt Schueller, and the MSDAvenir Fund (DEVO-DECODE project). The human embryonic and fetal material was provided by the Joint MRC-Wellcome (MR/R006237/1) Human Developmental Biology Resource (https://www.hdbr.org). We would like to thank S. Amat, F. Pelluard, and I. Deryabin for providing clinical information and material; M. Hibi (Nagoya University) for providing the zebrafish ptf1a probe; B. Crespo for technical help; and L. Colleaux for guidance during the course of the project. The authors declare no competing interests.
Funding Information:
The project is funded by the Agence Nationale de la Recherche ANR-16-CE12- 0005-01 , the Fondation pour la Recherche Médicale FRM-DEQ20160334938 , and the patient association CSC “ Connaître les syndromes Cérébelleux .” This work was also supported by state funding from the Agence Nationale de la Recherche under “Investissements d’avenir” program ( ANR-10-IAHU-01 ), the Fondation Bettencourt Schueller , and the MSDAvenir Fund (DEVO-DECODE project). The human embryonic and fetal material was provided by the Joint MRC-Wellcome (MR/R006237/1) Human Developmental Biology Resource ( https://www.hdbr.org ). We would like to thank S. Amat, F. Pelluard, and I. Deryabin for providing clinical information and material; M. Hibi (Nagoya University) for providing the zebrafish ptf1a probe; B. Crespo for technical help; and L. Colleaux for guidance during the course of the project.
Publisher Copyright:
© 2022 American Society of Human Genetics
PY - 2022/5/1
Y1 - 2022/5/1
N2 - Pontocerebellar hypoplasias (PCHs) are congenital disorders characterized by hypoplasia or early atrophy of the cerebellum and brainstem, leading to a very limited motor and cognitive development. Although over 20 genes have been shown to be mutated in PCHs, a large proportion of affected individuals remains undiagnosed. We describe four families with children presenting with severe neonatal brainstem dysfunction and pronounced deficits in cognitive and motor development associated with four different bi-allelic mutations in PRDM13, including homozygous truncating variants in the most severely affected individuals. Brain MRI and fetopathological examination revealed a PCH-like phenotype, associated with major hypoplasia of inferior olive nuclei and dysplasia of the dentate nucleus. Notably, histopathological examinations highlighted a sparse and disorganized Purkinje cell layer in the cerebellum. PRDM13 encodes a transcriptional repressor known to be critical for neuronal subtypes specification in the mouse retina and spinal cord but had not been implicated, so far, in hindbrain development. snRNA-seq data mining and in situ hybridization in humans show that PRDM13 is expressed at early stages in the progenitors of the cerebellar ventricular zone, which gives rise to cerebellar GABAergic neurons, including Purkinje cells. We also show that loss of function of prdm13 in zebrafish leads to a reduction in Purkinje cells numbers and a complete absence of the inferior olive nuclei. Altogether our data identified bi-allelic mutations in PRDM13 as causing a olivopontocerebellar hypoplasia syndrome and suggest that early deregulations of the transcriptional control of neuronal fate specification could contribute to a significant number of cases.
AB - Pontocerebellar hypoplasias (PCHs) are congenital disorders characterized by hypoplasia or early atrophy of the cerebellum and brainstem, leading to a very limited motor and cognitive development. Although over 20 genes have been shown to be mutated in PCHs, a large proportion of affected individuals remains undiagnosed. We describe four families with children presenting with severe neonatal brainstem dysfunction and pronounced deficits in cognitive and motor development associated with four different bi-allelic mutations in PRDM13, including homozygous truncating variants in the most severely affected individuals. Brain MRI and fetopathological examination revealed a PCH-like phenotype, associated with major hypoplasia of inferior olive nuclei and dysplasia of the dentate nucleus. Notably, histopathological examinations highlighted a sparse and disorganized Purkinje cell layer in the cerebellum. PRDM13 encodes a transcriptional repressor known to be critical for neuronal subtypes specification in the mouse retina and spinal cord but had not been implicated, so far, in hindbrain development. snRNA-seq data mining and in situ hybridization in humans show that PRDM13 is expressed at early stages in the progenitors of the cerebellar ventricular zone, which gives rise to cerebellar GABAergic neurons, including Purkinje cells. We also show that loss of function of prdm13 in zebrafish leads to a reduction in Purkinje cells numbers and a complete absence of the inferior olive nuclei. Altogether our data identified bi-allelic mutations in PRDM13 as causing a olivopontocerebellar hypoplasia syndrome and suggest that early deregulations of the transcriptional control of neuronal fate specification could contribute to a significant number of cases.
KW - Animals
KW - Brain Diseases/pathology
KW - Brain Stem
KW - Cerebellum/abnormalities
KW - Developmental Disabilities
KW - Histone-Lysine N-Methyltransferase/genetics
KW - Humans
KW - Mice
KW - Mutation/genetics
KW - Nervous System Malformations
KW - Neurogenesis/genetics
KW - Purkinje Cells/metabolism
KW - Transcription Factors/genetics
KW - Zebrafish/metabolism
UR - http://www.scopus.com/inward/record.url?scp=85129579312&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85129579312&partnerID=8YFLogxK
U2 - 10.1016/j.ajhg.2022.03.010
DO - 10.1016/j.ajhg.2022.03.010
M3 - Article
C2 - 35390279
AN - SCOPUS:85129579312
SN - 0002-9297
VL - 109
SP - 909
EP - 927
JO - American Journal of Human Genetics
JF - American Journal of Human Genetics
IS - 5
ER -