Recessive PRDM13 mutations cause fatal perinatal brainstem dysfunction with cerebellar hypoplasia and disrupt Purkinje cell differentiation

Coolen, Marion; Altin, Nami; Rajamani, Karthyayani; Pereira, Eva; Siquier-Pernet, Karine; Lombardi, Emilia Puig; Moreno, Nadjeda; Barcia, Giulia; Yvert, Marianne; Laquerrière, Annie; Pouliet, Aurore; Nitschké, Patrick; Boddaert, Nathalie; Rausell, Antonio; Razavi, F.; Afenjar, Alexandra; Villemeur, Thierry Billette de; Al‐Maawali, Almundher; Al‐Thihli, Khalid; Baptista, Júlia; Beleza-Meireles, Ana; Garel, Catherine; Legendre, Marine; Gelot, Antoinette; Bürglen, Lydie; Moutton, Sébastien; Cantagrel, Vincent

doi:10.1016/j.ajhg.2022.03.010

Cited by 11 publications

(15 citation statements)

References 56 publications

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“…Alternatively, we suggest that the small size of the cerebellar, and to some extent, neocortical organoids, may be caused by deficits in the proliferation of progenitor cells. Supporting the hypothesis that impaired proliferation and differentiation in the cerebellum leads to hypoplasia, bi-allelic variants in PRDM13 (OMIM * 6167441) cause cerebellar hypoplasia in humans (OMIM #619909) and loss of function of prdml3 disrupts Purkinje cell differentiation in zebrafish (Coolen et al, 2022). Moreover, altered development in several brain structures has been reported in human brain samples of a subtype of PCH (Patel et al, 2006).…”

Section: Discussionmentioning

confidence: 95%

Human organoid model of PCH2a recapitulates brain region-specific pathology

Kagermeier

Hauser

Sarieva

et al. 2022

Preprint

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Pontocerebellar hypoplasia type 2 a (PCH2a) is a rare, autosomal recessive neurogenetic disorder. Affected individuals present with early and severe neurological impairment. The anatomical hallmark of PCH2a is the hypoplasia of the cerebellum and pons accompanied by progressive microcephaly over the first years of life (OMIM #277470). Treatment options are limited and symptomatic. PCH2a results from a homozygous founder variant in the TSEN54 gene (OMIM *608755), which encodes a tRNA splicing endonuclease complex subunit. A recent study revealed altered tRNA pools in fibroblasts from affected individuals with PCH2a. However, the pathological mechanism underlying the hypoplasia of the cerebellum and the progressive microcephaly is unknown due to a lack of a model system. Leveraging recent progress in organoid generation, we developed human models of PCH2a using brain region-specific organoids. We, therefore, obtained skin biopsies from three affected males with genetically confirmed PCH2a and derived induced pluripotent stem cells (iPSCs). Cerebellar and neocortical organoids were differentiated from control and affected iPSCs and showed expression of TSEN54. In line with neuroimaging findings in affected individuals, PCH2a cerebellar organoids are reduced in size compared to controls starting early in differentiation. While neocortical PCH2a organoids also show growth deficits, they are less pronounced than those in cerebellar organoids, reminiscent of the progressive microcephaly in PCH2a. In addition, we do not find evidence of increased apoptosis in PCH2a organoids compared to controls in contrast to what has been suggested in loss-of-function animal models. We have generated a human model of PCH2a, which will allow to decipher disease mechanisms in depth in order to explain how a variant in a ubiquitously expressed gene involved in tRNA metabolism causes pathology in specific brain regions.

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Section: Discussionmentioning

confidence: 95%

Human organoid model of PCH2a recapitulates brain region-specific pathology

Kagermeier

Hauser

Sarieva

et al. 2022

Preprint

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“…Loss-of-function variants of PRDM13 on the other hand lead to severe syndromic phenotypes. 37 , 38 Given the evolutionary novelty of the macula in higher primates as an anatomically specialized cone-rich structure, it is attractive to speculate about the role of the CREs identified in the PRDM13 and IRX1 loci and implicated in NCMD as putative regulators of the relatively recent evolution of the macula. 93 Apart from non-coding SNVs, five NCMD-associated tandem duplications have also been identified in the PRDM13 locus.…”

Section: Discussionmentioning

confidence: 99%

“… 36 It should, however, be noted that recessive loss-of-function variants in PRDM13 have been associated with either hypogonadotropic hypogonadism or perinatal brainstem dysfunction, both in combination with cerebellar hypoplasia. 37 , 38 On the other hand, most vertebrate species possess six Iroquois ( IRX ) genes, located in two paralog clusters. These genes encode important developmental homeobox transcription factors, with key roles in regulating gene expression during pattern formation and nervous system development.…”

Section: Introductionmentioning

confidence: 99%

Multi-omics approach dissects cis-regulatory mechanisms underlying North Carolina macular dystrophy, a retinal enhanceropathy

Sompele¹,

Small²,

Cicekdal³

et al. 2022

The American Journal of Human Genetics

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“…P2X7R was found to have roles in neuroinflammation and implications in Alzheimer's disease pathogenesis 78 No published genotype–phenotype association 10DK3900 2 Years Male No Central hypoventilation and apnea, seizures, cerebellar vermis hypoplasia and early death PRDM13 PRDM13(NM_021620.4):c.800del (p.Gly267AspfsTer34) homozygous Yes NA Absent NA PRDM13 is implicated in transcriptional regulation. It is thought to be a vital component of a highly coordinated transcriptional network that determines the balance of inhibitory versus excitatory neurons in the dorsal spinal cord 79 Published 80 10MS13800 11 Years Female Yes Global developmental delay, extrapyramidal features and spasticity PTRHD1 PTRHD1(NM_001013663.2):c.169_196del (p.Ala57ArgfsTer26) homozygous Yes rs553276736 0.000541 NA Putative peptidyl-tRNA hydrolase with a PTH2 domain, implying that it works in the ubiquitin–proteasome pathway. It was suggested to be linked to early-onset parkinsonism and cognitive dysfunction 81 , 82 Published 83 10SS5400 4 Years Male Yes Hypotonia, global developmental delay, and seizures.…”

Section: Discussionmentioning

confidence: 99%

The diagnostic yield, candidate genes, and pitfalls for a genetic study of intellectual disability in 118 middle eastern families

Al‐Kasbi

Al-Murshedi

Al-Kindi

et al. 2022

Sci Rep

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Global Developmental Delay/Intellectual disability (ID) is the term used to describe various disorders caused by abnormal brain development and characterized by impairments in cognition, communication, behavior, or motor skills. In the past few years, whole-exome sequencing (WES) has been proven to be a powerful, robust, and scalable approach for candidate gene discoveries in consanguineous populations. In this study, we recruited 215 patients affected with ID from 118 Middle Eastern families. Whole-exome sequencing was completed for 188 individuals. The average age at which WES was completed was 8.5 years. Pathogenic or likely pathogenic variants were detected in 32/118 families (27%). Variants of uncertain significance were seen in 33/118 families (28%). The candidate genes with a possible association with ID were detected in 32/118 (27%) with a total number of 64 affected individuals. These genes are novel, were previously reported in a single family, or cause strikingly different phenotypes with a different mode of inheritance. These genes included: AATK, AP1G2, CAMSAP1, CCDC9B, CNTROB, DNAH14, DNAJB4, DRG1, DTNBP1, EDRF1, EEF1D, EXOC8, EXOSC4, FARSB, FBXO22, FILIP1, INPP4A, P2RX7, PRDM13, PTRHD1, SCN10A, SCYL2, SMG8, SUPV3L1, TACC2, THUMPD1, XPR1, ZFYVE28. During the 5 years of the study and through gene matching databases, several of these genes have now been confirmed as causative of ID. In conclusion, understanding the causes of ID will help understand biological mechanisms, provide precise counseling for affected families, and aid in primary prevention.

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Recessive PRDM13 mutations cause fatal perinatal brainstem dysfunction with cerebellar hypoplasia and disrupt Purkinje cell differentiation

Cited by 11 publications

References 56 publications

Human organoid model of PCH2a recapitulates brain region-specific pathology

Human organoid model of PCH2a recapitulates brain region-specific pathology

Multi-omics approach dissects cis-regulatory mechanisms underlying North Carolina macular dystrophy, a retinal enhanceropathy

The diagnostic yield, candidate genes, and pitfalls for a genetic study of intellectual disability in 118 middle eastern families

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