title: CCDC88A mutations cause PEHO-like syndrome in humans and mouse.
abstract: Progressive encephalopathy with oedema, hypsarrhythmia and optic atrophy (PEHO) syndrome is a rare Mendelian phenotype comprising severe retardation, early onset epileptic seizures, optic nerve/cerebellar atrophy, pedal oedema, and early death. Atypical cases are often known as PEHO-like, and there is an overlap with 'early infantile epileptic encephalopathy'. PEHO is considered to be recessive, but surprisingly since initial description in 1991, no causative recessive gene(s) have been described. Hence, we report a multiplex consanguineous family with the PEHO phenotype where affected individuals had a homozygous frame-shift deletion in CCDC88A (c.2313delT, p.Leu772*ter). Analysis of cDNA extracted from patient lymphocytes unexpectedly failed to show non-sense mediated decay, and we demonstrate that the mutation produces a truncated protein lacking the crucial C-terminal half of CCDC88A (girdin). To further investigate the possible role of CCDC88A in human neurodevelopment we re-examined the behaviour and neuroanatomy of Ccdc88a knockout pups. These mice had mesial-temporal lobe epilepsy, microcephaly and corpus callosum deficiency, and by postnatal Day 21, microcephaly; the mice died at an early age. As the mouse knockout phenotype mimics the human PEHO phenotype this suggests that loss of CCDC88A is a cause of the PEHO phenotype, and that CCDC88A is essential for multiple aspects of normal human neurodevelopment.
authors.affiliation: Cambridge Institute for Medical Research, University of Cambridge, Cambridge, CB2 0XY, UK.
authors.forename: Michael S
authors.initials: MS
authors.lastname: Nahorski
authors.affiliation: Department of Pathology, Centre for Neurological Disease and Cancer, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya, Aichi, 466N, Japan.
authors.forename: Masato
authors.initials: M
authors.lastname: Asai
authors.affiliation: North West Thames Regional Genetics Service, Level 8V, London North West Healthcare NHS Trust, Watford Road, Harrow, HA1 3UJ, UK.
authors.forename: Emma
authors.initials: E
authors.lastname: Wakeling
authors.affiliation: Department of Paediatric Neuroscience, Addenbrooke's Hospital, Hills Rd, Cambridge, CB2 0QQ, UK.
authors.forename: Alasdair
authors.initials: A
authors.lastname: Parker
authors.affiliation: Department of Pathology, Centre for Neurological Disease and Cancer, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya, Aichi, 466N, Japan.
authors.forename: Naoya
authors.initials: N
authors.lastname: Asai
authors.affiliation: North West Thames Regional Genetics Service, Level 8V, London North West Healthcare NHS Trust, Watford Road, Harrow, HA1 3UJ, UK.
authors.forename: Natalie
authors.initials: N
authors.lastname: Canham
authors.affiliation: North West Thames Regional Genetics Service, Level 8V, London North West Healthcare NHS Trust, Watford Road, Harrow, HA1 3UJ, UK.
authors.forename: Susan E
authors.initials: SE
authors.lastname: Holder
authors.affiliation: Cambridge Institute for Medical Research, University of Cambridge, Cambridge, CB2 0XY, UK.
authors.forename: Ya-Chun
authors.initials: YC
authors.lastname: Chen
authors.affiliation: Cambridge Institute for Medical Research, University of Cambridge, Cambridge, CB2 0XY, UK.
authors.forename: Joshua
authors.initials: J
authors.lastname: Dyer
authors.affiliation: North West Thames Regional Genetics Service, Level 8V, London North West Healthcare NHS Trust, Watford Road, Harrow, HA1 3UJ, UK cw347@cam.ac.uk angela.brady@nhs.net mtakaha@med.nagoya-u.ac.jp.
authors.forename: Angela F
authors.initials: AF
authors.lastname: Brady
authors.affiliation: Department of Pathology, Centre for Neurological Disease and Cancer, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya, Aichi, 466N, Japan cw347@cam.ac.uk angela.brady@nhs.net mtakaha@med.nagoya-u.ac.jp.
authors.forename: Masahide
authors.initials: M
authors.lastname: Takahashi
authors.affiliation: Cambridge Institute for Medical Research, University of Cambridge, Cambridge, CB2 0XY, UK cw347@cam.ac.uk angela.brady@nhs.net mtakaha@med.nagoya-u.ac.jp.
authors.forename: C Geoffrey
authors.initials: CG
authors.lastname: Woods
mesh_terms: D000818:Animals; D001921:Brain / Q000473:pathology; D001929:Brain Edema / Q000175:diagnosis* / Q000235:genetics*; D002648:Child; D005260:Female; D006801:Humans; D007223:Infant; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008840:Microfilament Proteins / Q000235:genetics*; D009154:Mutation / Q000235:genetics*; D019636:Neurodegenerative Diseases / Q000175:diagnosis* / Q000235:genetics*; D009896:Optic Atrophy / Q000175:diagnosis* / Q000235:genetics*; D010375:Pedigree; D013036:Spasms, Infantile / Q000175:diagnosis* / Q000235:genetics*; D033921:Vesicular Transport Proteins / Q000235:genetics*
chemical_list: C502451:CCDC88A protein, human; D008840:Microfilament Proteins; D033921:Vesicular Transport Proteins
keywords: PEHO syndrome; epilepsy; girdin; microcephaly; neurodevelopmental disorder