Bi-allelic loss-of-function variants in PPFIBP1 cause a neurodevelopmental disorder with microcephaly, epilepsy, and periventricular calcifications

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Rosenhahn, ErikInstitute of Human Genetics, University of Leipzig Medical Center, Germany (författare)

Bi-allelic loss-of-function variants in PPFIBP1 cause a neurodevelopmental disorder with microcephaly, epilepsy, and periventricular calcifications

Artikel/kapitelEngelska2022

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Cell Press,2022
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LIBRIS-ID:oai:DiVA.org:his-21694
https://urn.kb.se/resolve?urn=urn:nbn:se:his:diva-21694URI
https://doi.org/10.1016/j.ajhg.2022.06.008DOI
http://kipublications.ki.se/Default.aspx?queryparsed=id:150656596URI

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Språk:engelska
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CC BY 4.0© 2022 The AuthorsCorrespondence: andre.brown@lms.mrc.ac.uk (A.E.X.B.), konrad.platzer@medizin.uni-leipzig.de (K.P.)We thank all families that participated in this study. This project has received funding from the European Research Council under the European External Action Service Horizon 2020 Research and Innovation Program (grant agreement no. 714853) and was supported by the Medical Research Council through grant MC-A658-5TY30. H.T. was supported by the European External Action Service Seventh Framework Programme for research, technological development, and demonstration under grant agreement no. 608473.
PPFIBP1 encodes for the liprin-β1 protein, which has been shown to play a role in neuronal outgrowth and synapse formation in Drosophila melanogaster. By exome and genome sequencing, we detected nine ultra-rare homozygous loss-of-function variants in 16 individuals from 12 unrelated families. The individuals presented with moderate to profound developmental delay, often refractory early-onset epilepsy, and progressive microcephaly. Further common clinical findings included muscular hyper- and hypotonia, spasticity, failure to thrive and short stature, feeding difficulties, impaired vision, and congenital heart defects. Neuroimaging revealed abnormalities of brain morphology with leukoencephalopathy, ventriculomegaly, cortical abnormalities, and intracranial periventricular calcifications as major features. In a fetus with intracranial calcifications, we identified a rare homozygous missense variant that by structural analysis was predicted to disturb the topology of the SAM domain region that is essential for protein-protein interaction. For further insight into the effects of PPFIBP1 loss of function, we performed automated behavioral phenotyping of a Caenorhabditis elegans PPFIBP1/hlb-1 knockout model, which revealed defects in spontaneous and light-induced behavior and confirmed resistance to the acetylcholinesterase inhibitor aldicarb, suggesting a defect in the neuronal presynaptic zone. In conclusion, we establish bi-allelic loss-of-function variants in PPFIBP1 as a cause of an autosomal recessive severe neurodevelopmental disorder with early-onset epilepsy, microcephaly, and periventricular calcifications.

Ämnesord och genrebeteckningar

MEDICIN OCH HÄLSOVETENSKAP Medicinska och farmaceutiska grundvetenskaper Medicinsk genetik hsv//swe
MEDICAL AND HEALTH SCIENCES Basic Medicine Medical Genetics hsv//eng
MEDICIN OCH HÄLSOVETENSKAP Klinisk medicin Klinisk laboratoriemedicin hsv//swe
MEDICAL AND HEALTH SCIENCES Clinical Medicine Clinical Laboratory Medicine hsv//eng
MEDICIN OCH HÄLSOVETENSKAP Klinisk medicin Neurologi hsv//swe
MEDICAL AND HEALTH SCIENCES Clinical Medicine Neurology hsv//eng
MEDICIN OCH HÄLSOVETENSKAP Medicinsk bioteknologi Biomedicinsk laboratorievetenskap/teknologi hsv//swe
MEDICAL AND HEALTH SCIENCES Medical Biotechnology Biomedical Laboratory Science/Technology hsv//eng
MEDICIN OCH HÄLSOVETENSKAP Medicinska och farmaceutiska grundvetenskaper Cell- och molekylärbiologi hsv//swe
MEDICAL AND HEALTH SCIENCES Basic Medicine Cell and Molecular Biology hsv//eng
Acetylcholinesterase
Animals
Drosophila melanogaster
Epilepsy
Loss of Heterozygosity
Microcephaly
Nervous System Malformations
Neurodevelopmental Disorders
Pedigree
animal
genetics
heterozygosity loss
mental disease
nervous system malformation
Translationell medicin TRIM
Translational Medicine TRIM

Biuppslag (personer, institutioner, konferenser, titlar ...)

O'Brien, Thomas J.MRC London Institute of Medical Sciences, United Kingdom (författare)
Zaki, Maha S.Clinical Genetics Department, Human Genetics and Genome Research Institute, National Research Centre, Cairo, Egypt (författare)
Sorge, InaDepartment of Pediatric Radiology, University Hospital Leipzig, Germany (författare)
Wieczorek, DagmarInstitute of Human Genetics, Medical Faculty and University Hospital Düsseldorf, Heinrich-Heine-University Düsseldorf, Germany (författare)
Rostasy, KevinDepartment of Pediatric Neurology, Children's and Adolescents’ Hospital Datteln, Witten/Herdecke University, Germany (författare)
Vitobello, AntonioUF6254 Innovation en Diagnostic Genomique des Maladies Rares, CHU Dijon Bourgogne, FHU translad, Génétique des Anomalies du Développement, INSERM UMR 1231, Université de Bourgogne-Franche Comté, Dijon, France (författare)
Nambot, SophieCentre de Génétique et Centre de référence des Maladies rare, Anomalies du Développement et Syndromes Malformatifs, Hôpital d'Enfants, Centre Hospitalier Universitaire de Dijon, France (författare)
Alkuraya, Fowsan S.Department of Translational Genomics, Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia ; Department of Anatomy and Cell Biology, College of Medicine, Alfaisal University, Riyadh, Saudi Arabia (författare)
Hashem, Mais O.Department of Translational Genomics, Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia (författare)
Alhashem, AmalKarolinska Institutet (författare)
Tabarki, BrahimDepartment of Pediatrics, Prince Sultan Military Medical City, Riyadh, Saudi Arabia (författare)
Alamri, Abdullah S.Department of Pediatrics, Imam Abdulrahman bin Faisal University, Dammam, Saudi Arabia (författare)
Al Safar, Ayat H.Department of Pediatrics, Imam Abdulrahman bin Faisal University, Dammam, Saudi Arabia (författare)
Bubshait, Dalal K.Department of Pediatrics, Imam Abdulrahman bin Faisal University, Dammam, Saudi Arabia (författare)
Alahmady, Nada F.Biology Department, Imam Abdulrahman bin Faisal University, Dammam, Saudi Arabia (författare)
Gleeson, Joseph G.Department of Neurosciences, University of California, San Diego, La Jolla, CA, USA ; Rady Children’s Institute for Genomic Medicine, San Diego, La Jolla, CA, USA (författare)
Abdel-Hamid, Mohamed S.Medical Molecular Genetics Department, Human Genetics and Genome Research Institute, National Research Centre, Cairo, Egypt (författare)
Lesko, NicoleDepartment of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden ; Centre for Inherited Metabolic Diseases, Karolinska University Hospital, Stockholm, Sweden (författare)
Ygberg, SofiaKarolinska Institutet (författare)
Correia, Sandrina P.Karolinska Institutet (författare)
Wredenberg, AnnaDepartment of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden ; Centre for Inherited Metabolic Diseases, Karolinska University Hospital, Stockholm, Sweden (författare)
Alavi, ShahryarDepartment of Cell and Molecular Biology and Microbiology, Faculty of Biological Science and Technology, University of Isfahan, Iran ; Palindrome, Isfahan, Iran (författare)
Seyedhassani, Seyed M.Dr. Seyedhassani Medical Genetic Center, Yazd, Iran (författare)
Ebrahimi Nasab, MahyaDr. Seyedhassani Medical Genetic Center, Yazd, Iran (författare)
Hussien, HaythamAlexandria University Children’s Hospital, Faculty of Medicine, Alexandria University, Egypt (författare)
Omar, Tarek E. I.Alexandria University Children’s Hospital, Faculty of Medicine, Alexandria University, Egypt (författare)
Harzallah, InesClinical, Chromosomal and Molecular Genetics Department, University Hospital Center, Saint-Étienne, France (författare)
Touraine, RenaudClinical, Chromosomal and Molecular Genetics Department, University Hospital Center, Saint-Étienne, France (författare)
Tajsharghi, HomaHögskolan i Skövde,Institutionen för hälsovetenskaper,Forskningsmiljön hälsa, hållbarhet och digitalisering,Translationell medicin TRIM, Translational Medicine(Swepub:his)tajh (författare)
Morsy, HebaUCL Queen Square Institute of Neurology, University College London, UK (författare)
Houlden, HenryUCL Queen Square Institute of Neurology, University College London, UK (författare)
Shahrooei, MohammadSpecialized Immunology Laboratory of Dr. Shahrooei, Sina Medical Complex, Ahvaz, Iran ; Department of Microbiology and Immunology, Clinical and Diagnostic Immunology, KU Leuven, Belgium (författare)
Ghavideldarestani, MaryamSpecialized Immunology Laboratory of Dr. Shahrooei, Sina Medical Complex, Ahvaz, Iran (författare)
Abdel-Salam, Ghada M. H.Clinical Genetics Department, Human Genetics and Genome Research Institute, National Research Centre, Cairo, Egypt (författare)
Torella, AnnalauraDepartment of Precision Medicine, University of Campania Luigi Vanvitelli, Naples, Italy ; Telethon Institute of Genetics and Medicine, Naples, Italy (författare)
Zanobio, MariateresaDepartment of Precision Medicine, University of Campania Luigi Vanvitelli, Naples, Italy (författare)
Terrone, GaetanoChild Neurology Unit, Department of Translational Medical Science, University of Naples Federico II, Naples, Italy (författare)
Brunetti-Pierri, NicolaTelethon Institute of Genetics and Medicine, Naples, Italy ; Department of Translational Medicine, Section of Pediatrics, University of Naples Federico II, Italy (författare)
Omrani, AbdolmajidDivision of Clinical Studies, The Persian Gulf Nuclear Medicine Research Center, Bushehr University of Medical Sciences, Iran (författare)
Hentschel, JuliaInstitute of Human Genetics, University of Leipzig Medical Center, Leipzig, Germany (författare)
Lemke, Johannes R.Institute of Human Genetics, University of Leipzig Medical Center, Germany ; Center for Rare Diseases, University of Leipzig Medical Center, Germany (författare)
Sticht, HeinrichInstitute of Biochemistry, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany (författare)
Abou Jamra, RamiInstitute of Human Genetics, University of Leipzig Medical Center, Germany (författare)
Brown, Andre E. X.MRC London Institute of Medical Sciences, UK ; Faculty of Medicine, Institute of Clinical Sciences, Imperial College London, UK ; (författare)
Maroofian, RezaUCL Queen Square Institute of Neurology, University College London, UK (författare)
Platzer, KonradInstitute of Human Genetics, University of Leipzig Medical Center, Germany (författare)
Institute of Human Genetics, University of Leipzig Medical Center, GermanyMRC London Institute of Medical Sciences, United Kingdom (creator_code:org_t)

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Ingår i:American Journal of Human Genetics: Cell Press109:8, s. 1421-14350002-92971537-6605

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Av författaren/redakt...: Rosenhahn, Erik; O'Brien, Thomas ...; Zaki, Maha S.; Sorge, Ina; Wieczorek, Dagma ...; Rostasy, Kevin; visa fler...; Vitobello, Anton ...; Nambot, Sophie; Alkuraya, Fowsan ...; Hashem, Mais O.; Alhashem, Amal; Tabarki, Brahim; Alamri, Abdullah ...; Al Safar, Ayat H ...; Bubshait, Dalal ...; Alahmady, Nada F ...; Gleeson, Joseph ...; Abdel-Hamid, Moh ...; Lesko, Nicole; Ygberg, Sofia; Correia, Sandrin ...; Wredenberg, Anna; Alavi, Shahryar; Seyedhassani, Se ...; Ebrahimi Nasab, ...; Hussien, Haytham; Omar, Tarek E. I ...; Harzallah, Ines; Touraine, Renaud; Tajsharghi, Homa; Morsy, Heba; Houlden, Henry; Shahrooei, Moham ...; Ghavideldarestan ...; Abdel-Salam, Gha ...; Torella, Annalau ...; Zanobio, Mariate ...; Terrone, Gaetano; Brunetti-Pierri, ...; Omrani, Abdolmaj ...; Hentschel, Julia; Lemke, Johannes ...; Sticht, Heinrich; Abou Jamra, Rami; Brown, Andre E. ...; Maroofian, Reza; Platzer, Konrad; visa färre...

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