CCDC88A mutations cause PEHO-like syndrome in humans and mouse

Nahorski, Michael S.; Asai, Masato; Wakeling, Emma; Parker, Alasdair; Asai, Naoya; Canham, Natalie; Holder, Susan; Chen, Ya Chun; Dyer, J.; Brady, Angela; Takahashi, Masahide; Woods, C. Geoffrey

doi:10.1093/brain/aww014

Cited by 23 publications

(28 citation statements)

References 30 publications

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“…Since the original clinical description of this condition in 1991, a number of different genes and modes of inheritance have been associated with clinical presentations said to be consistent with PEHO, or thought to be PEHO-like in nature, including de novo dominant variants in CDKL5 and KIF1A and biallelic mutations in CCDC8A (Gawlinski et al , 2016; Langlois et al , 2016; Nahorski et al , 2016) . The phenotype in the Italian family, as well as consistent overlapping clinical aspects present in the other families described here, provides cause to consider that PRUNE1 should now also be added to the list of genes in which mutations may present in children with epileptic encephalopathy and PEHO-like features.…”

Section: Discussionmentioning

confidence: 99%

PRUNE is crucial for normal brain development and mutated in microcephaly with neurodevelopmental impairment

Zollo

Ahmed

Ferrucci

et al. 2017

Brain

112

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Section: Discussionmentioning

confidence: 99%

PRUNE is crucial for normal brain development and mutated in microcephaly with neurodevelopmental impairment

Zollo

Ahmed

Ferrucci

et al. 2017

Brain

112

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“…Within a consanguineous family, two siblings and a cousin had a PEHO-like condition, which we have previously described 31. The affected children had a homozygous, and the parents the heterozygous variant, c.2313delT, p.Leu772*ter in the gene CCDC88A.…”

Section: Resultsmentioning

confidence: 94%

“…The ThiF domain of UBA5 is shown as a white box. See Nahorski et al 31 for family tree for family C and illustration of CCDC88A variants. Family tree for family A and variants in the PCLO gene and its protein.…”

Section: Resultsmentioning

confidence: 99%

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PEHO syndrome: the endpoint of different genetic epilepsies

et al. 2018

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BackgroundProgressive encephalopathy, hypsarrhythmia and optic atrophy (PEHO) has been described as a clinically distinct syndrome. It has been postulated that it is an autosomal recessive condition. However, the aetiology is poorly understood, and the genetic basis of the condition has not been fully elucidated. Our objective was to discover if PEHO syndrome is a single gene disorder.MethodChildren with PEHO and PEHO-like syndrome were recruited. Clinical, neurological and dysmorphic features were recorded; EEG reports and MRI scans were reviewed. Where possible, exome sequencing was carried out first to seek mutations in known early infantile developmental and epileptic encephalopathy (DEE) genes and then to use an agnostic approach to seek novel candidate genes. We sought intra–interfamilial phenotypic correlations and genotype–phenotype correlations when pathological mutations were identified.ResultsTwenty-three children were recruited from a diverse ethnic background, 19 of which were suitable for inclusion. They were similar in many of the core and the supporting features of PEHO, but there was significant variation in MRI and ophthalmological findings, even between siblings with the same mutation. A pathogenic genetic variant was identified in 15 of the 19 children. One further girl’s DNA failed analysis, but her two affected sisters shared confirmed variants. Pathogenic variants were identified in seven different genes.ConclusionsWe found significant clinical and genetic heterogeneity. Given the intrafamily variation demonstrated, we question whether the diagnostic criteria for MRI and ophthalmic findings should be altered. We also question whether PEHO and PEHO-like syndrome represent differing points on a clinical spectrum of the DEE. We conclude that PEHO and PEHO-like syndrome are clinically and genetically diverse entities—and are phenotypic endpoints of many severe genetic encephalopathies.

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“…Their roles in brain development have not been fully explored, but Girdin can promote long-range neuronal migration by affecting cell adhesion and, separately, can affect synaptic plasticity (Enomoto et al, 2009;Wang et al, 2011;Nakai et al, 2014;Itoh et al, 2016). Loss of Girdin/CCDC88A causes PEHO syndrome, characterized by progressive encephalopathy and optic atrophy (Nahorski et al, 2016). Intriguingly, loss of CCDC88C leads to congenital hydrocephalus similar to that seen in loss of L1CAM/SAX-7 (Ekici et al, 2010;Drielsma et al, 2012;Ruggeri et al, 2018), although no relationship between CCDC88C and L1CAM has been identified previously.…”

Section: Grdn-1mentioning

confidence: 99%

Dendrites with specialized glial attachments develop by retrograde extension using SAX-7 and GRDN-1

Cebul

McLachlan

Heiman

2019

Preprint

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Dendrites develop elaborate morphologies in concert with surrounding glia, but the molecules that coordinate dendrite and glial morphogenesis are mostly unknown. C. elegans offers a powerful model for identifying such factors. Previous work in this system examined dendrites and glia that develop within epithelia, similar to mammalian sense organs. Here, we focus on the neurons BAG and URX, which are not part of an epithelium but instead form membranous attachments to a single glial cell at the nose, reminiscent of dendrite-glia contacts in the mammalian brain. We show that these dendrites develop by retrograde extension, in which the nascent dendrite endings anchor to the presumptive nose and then extend by stretch during embryo elongation. Using forward genetic screens, we find that dendrite development requires the adhesion protein SAX-7/L1CAM and the cytoplasmic protein GRDN-1/CCDC88C to anchor dendrite endings at the nose. SAX-7 acts in neurons and glia, while GRDN-1 acts in glia to nonautonomously promote dendrite extension. Thus, this work shows how glial factors can help to shape dendrites, and identifies a novel molecular mechanism for dendrite growth by retrograde extension.C. elegans offers several advantages. Each cell can be uniquely identified and has a remarkably stereotyped shape and set of cell-cell contacts; neuron-and glia-specific promoters allow the targeted expression of transgenes in single cells to visualize and manipulate specific neuron-glia contacts in intact living animals; and its powerful genetics permit unbiased screens to identify factors that control neuron-glia interactions. Additionally, C. elegans glia share a number of important features with mammalian glia (Mizeracka and Heiman, 2015). This system Retrograde extension by SAX-7 and GRDN-1 4 thus offers a powerful genetic model for dissecting dendrite-glia contacts. Here, we turned our attention to a previously overlooked class of dendrite-glia contacts whose elaborate, tightly apposed membranous structures are reminiscent of the highly coordinated membranous contacts found between astrocytes and dendritic spines at mammalian synapses.Using super-resolution microscopy, we find that the dendrites of two neuron types, URX and BAG, form specialized attachments with a single glial partner. Using forward genetics, we identify two conserved molecules, SAX-7 and GRDN-1, that are required for the development of these dendrites. SAX-7 is a homolog of the mammalian neuron-glia adhesion molecule L1CAM, and GRDN-1 is a homolog of proteins involved in cell polarity and cytoskeleton organization.Each of these homologs is expressed in the mammalian brain and causes developmental brain disorders when disrupted (Jouet et al., 1994;Vits et al., 1994; Ekici et al., 2010). Using embryonic time-course imaging, we find that URX and BAG dendrites develop by retrograde extension, a type of outgrowth in which the dendrites anchor to their targets and then extend by stretch. SAX-7 and GRDN-1 help to anchor dendrite endings at the nose during embryo elong...

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CCDC88A mutations cause PEHO-like syndrome in humans and mouse

Cited by 23 publications

References 30 publications

PRUNE is crucial for normal brain development and mutated in microcephaly with neurodevelopmental impairment

PRUNE is crucial for normal brain development and mutated in microcephaly with neurodevelopmental impairment

PEHO syndrome: the endpoint of different genetic epilepsies

Dendrites with specialized glial attachments develop by retrograde extension using SAX-7 and GRDN-1

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