CCDC88A mutations cause PEHO-like syndrome in humans and mouse

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.This work was supported by the MRC and Cambridge University Hospitals NHS Foundation Trust (MSN), YCC and CGW are supported by the Cambridge NIHR Biomedical Research Centre. This work was also supported by A-STEP from the Japan Science and Technology Agency in 2014 (AS251Z02522Q) and in 2015 (AS262Z00715Q), a Takeda Visionary Research Grant 2014 from the Takeda Science Foundation, a Grant-in-Aid for Scientific Research (C) (to M.A.), and a Grant-in-Aid for Scientific Research (S) (to MT) from the Ministry of Education, Culture, Sports, Science, and Technology in Japan.This is the final version of the article. It first appeared from Oxford University Press via http://dx.doi.org/10.1093/brain/aww01