Loss of Protocadherin-12 Leads to Diencephalic-Mesencephalic Junction Dysplasia Syndrome.

Autor:	Guemez-Gamboa A; Howard Hughes Medical Institute, Laboratory for Pediatric Brain Disease, Rockefeller University, New York, NY., Çağlayan AO; Department of Neurosurgery, Yale School of Medicine, New Haven, CT., Stanley V; Department of Neurosciences, University of California, San Diego, La Jolla, CA., Gregor A; Howard Hughes Medical Institute, Laboratory for Pediatric Brain Disease, Rockefeller University, New York, NY., Zaki MS; Department of Clinical Genetics, National Research Centre, Cairo, Egypt., Saleem SN; Radiology Department-Faculty of Medicine, Cairo University, Cairo, Egypt., Musaev D; Department of Neurosciences, University of California, San Diego, La Jolla, CA., McEvoy-Venneri J; Department of Neurosciences, University of California, San Diego, La Jolla, CA., Belandres D; Department of Neurosciences, University of California, San Diego, La Jolla, CA., Akizu N; Department of Neurosciences, University of California, San Diego, La Jolla, CA., Silhavy JL; Department of Neurosciences, University of California, San Diego, La Jolla, CA., Schroth J; Department of Neurosciences, University of California, San Diego, La Jolla, CA., Rosti RO; Howard Hughes Medical Institute, Laboratory for Pediatric Brain Disease, Rockefeller University, New York, NY., Copeland B; Howard Hughes Medical Institute, Laboratory for Pediatric Brain Disease, Rockefeller University, New York, NY., Lewis SM; Howard Hughes Medical Institute, Laboratory for Pediatric Brain Disease, Rockefeller University, New York, NY., Fang R; Howard Hughes Medical Institute, Laboratory for Pediatric Brain Disease, Rockefeller University, New York, NY., Issa MY; Department of Clinical Genetics, National Research Centre, Cairo, Egypt., Per H; Department of Paediatrics, Division of Paediatric Neurology, School of Medicine, Erciyes University, Kayseri, Turkey., Gumus H; Department of Paediatrics, Division of Paediatric Neurology, School of Medicine, Erciyes University, Kayseri, Turkey., Bayram AK; Department of Paediatrics, Division of Paediatric Neurology, School of Medicine, Erciyes University, Kayseri, Turkey., Kumandas S; Department of Paediatrics, Division of Paediatric Neurology, School of Medicine, Erciyes University, Kayseri, Turkey., Akgumus GT; Departments of Neurosurgery, Neurobiology and Genetics, Yale School of Medicine, New Haven, CT., Erson-Omay EZ; Departments of Neurosurgery, Neurobiology and Genetics, Yale School of Medicine, New Haven, CT., Yasuno K; Departments of Neurosurgery, Neurobiology and Genetics, Yale School of Medicine, New Haven, CT., Bilguvar K; Departments of Neurosurgery, Neurobiology and Genetics, Yale School of Medicine, New Haven, CT., Heimer G; Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel., Pillar N; Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel., Shomron N; Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel., Weissglas-Volkov D; Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel., Porat Y; Genoox, Tel Aviv, Israel., Einhorn Y; Genoox, Tel Aviv, Israel., Gabriel S; Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, MA., Ben-Zeev B; Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel., Gunel M; Department of Neurosurgery, Yale School of Medicine, New Haven, CT., Gleeson JG; Howard Hughes Medical Institute, Laboratory for Pediatric Brain Disease, Rockefeller University, New York, NY.; Department of Neurosciences, University of California, San Diego, La Jolla, CA.
Jazyk:	angličtina
Zdroj:	Annals of neurology [Ann Neurol] 2018 Nov; Vol. 84 (5), pp. 638-647. Date of Electronic Publication: 2018 Oct 04.
DOI:	10.1002/ana.25327
Abstrakt:	Objective: To identify causes of the autosomal-recessive malformation, diencephalic-mesencephalic junction dysplasia (DMJD) syndrome. Methods: Eight families with DMJD were studied by whole-exome or targeted sequencing, with detailed clinical and radiological characterization. Patient-derived induced pluripotent stem cells were derived into neural precursor and endothelial cells to study gene expression. Results: All patients showed biallelic mutations in the nonclustered protocadherin-12 (PCDH12) gene. The characteristic clinical presentation included progressive microcephaly, craniofacial dysmorphism, psychomotor disability, epilepsy, and axial hypotonia with variable appendicular spasticity. Brain imaging showed brainstem malformations and with frequent thinned corpus callosum with punctate brain calcifications, reflecting expression of PCDH12 in neural and endothelial cells. These cells showed lack of PCDH12 expression and impaired neurite outgrowth. Interpretation: DMJD patients have biallelic mutations in PCDH12 and lack of protein expression. These patients present with characteristic microcephaly and abnormalities of white matter tracts. Such pathogenic variants predict a poor outcome as a result of brainstem malformation and evidence of white matter tract defects, and should be added to the phenotypic spectrum associated with PCDH12-related conditions. Ann Neurol 2018;84:646-655. (© 2018 American Neurological Association.)
Databáze:	MEDLINE
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