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Investigating the etiologies of non-malarial febrile illness in Senegal using metagenomic sequencing

NATURE COMMUNICATIONS 2024年第1期15卷 747页

作者： Levine, Zoe C. Sene, Aita Mkandawire, Winnie Deme, Awa B. Ndiaye, Tolla Sy, Mouhamad Gaye, Amy Diedhiou, Younouss Mbaye, Amadou M. Ndiaye, Ibrahima M. Gomis, Jules Ndiop, Medoune Sene, Doudou Faye Paye, Marietou Macinnis, Bronwyn L. Schaffner, Stephen F. Park, Daniel J. Badiane, Aida S. Colubri, Andres Ndiaye, Mouhamadou Sy, Ngayo Sabeti, Pardis C. Ndiaye, Daouda Siddle, Katherine J. Broad Inst Harvard & MIT Cambridge MA 02142 USA Harvard Grad Program Biol & Biomed Sci Boston MA USA Harvard MIT MD PhD Program Boston MA USA Cheikh Anta Diop Univ Dakar Dept Parasitol Dakar Senegal Ctr Int Rech & Format Genomique Appl & Surveillanc Dakar Senegal Univ Massachusetts Med Sch Worcester MA USA Minist Sante Programme Natl Lutte Paludisme Dakar Senegal Harvard Univ Harvard TH Chan Sch Publ Hlth Dept Immunol & Infect Dis Boston MA 02138 USA Harvard Univ Dept Organism & Evolutionary Biol Cambridge MA 02138 USA Serv Lutte Anti Parasitaire Thies Senegal Howard Hughes Med Inst Chevy Chase MD 20815 USA Brown Univ Dept Mol Microbiol & Immunol Providence RI 02912 USA

The worldwide decline in malaria incidence is revealing the extensive burden of non-malarial febrile illness (NMFI), which remains poorly understood and difficult to diagnose. To characterize NMFI in Senegal, we collected venous blood and clinical metadata in a cross-sectional study of febrile patients and healthy controls in a low malaria burden area. Using 16S and untargeted sequencing, we detected viral, bacterial, or eukaryotic pathogens in 23% (38/163) of NMFI cases. Bacteria were the most common, with relapsing fever Borrelia and spotted fever Rickettsia found in 15.5% and 3.8% of cases, respectively. Four viral pathogens were found in a total of 7 febrile cases (3.5%). Sequencing also detected undiagnosed Plasmodium, including one putative P. ovale infection. We developed a logistic regression model that can distinguish Borrelia from NMFIs with similar presentation based on symptoms and vital signs (F1 score: 0.823). These results highlight the challenge and importance of improved diagnostics, especially for Borrelia, to support diagnosis and surveillance. Non-malarial febrile illnesses have a range of potential aetiologies which are difficult to diagnose and therefore treat. Here, the authors investigate the causes of acute febrile illness in a peri-urban area of Senegal with low malaria incidence using untargeted and targeted sequencing methods.

关键词： Microbial genetics Infectious diseases Genomics

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Metabolism and Colorectal Cancer

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Pathology: Mechanisms of Disease 1000年第1期18卷 467-492页

作者： Joseph C. Sedlak Ömer H. Yilmaz Jatin Roper 2Harvard/MIT MD-PhD Program Harvard Medical School Boston Massachusetts USA 1The David H. Koch Institute for Integrative Cancer Research at MIT Department of Biology Massachusetts Institute of Technology Cambridge Massachusetts USA email: ohyilmaz@mit.edu 3Massachusetts General Hospital Department of Pathology Boston Massachusetts USA 5Department of Pharmacology and Cancer Biology Duke University Durham North Carolina USA 4Division of Gastroenterology Department of Medicine Duke University Durham North Carolina USA email: jatin.roper@duke.edu

Reprogrammed metabolism is a hallmark of colorectal cancer (CRC). CRC cells are geared toward rapid proliferation, requiring nutrients and the removal of cellular waste in nutrient-poor environments. Intestinal stem cells (ISCs), the primary cell of origin for CRCs, must adapt their metabolism along the adenoma-carcinoma sequence to the unique features of their complex microenvironment that include interactions with intestinal epithelial cells, immune cells, stromal cells, commensal microbes, and dietary components. Emerging evidence implicates modifiable risk factors related to the environment, such as diet, as important in CRC pathogenesis. Here, we focus on describing the metabolism of ISCs, diets that influence CRC initiation, CRC genetics and metabolism, and the tumor microenvironment. The mechanistic links between environmental factors, metabolic adaptations, and the tumor microenvironment in enhancing or supporting CRC tumorigenesis are becoming better understood. Thus, greater knowledge of CRC metabolism holds promise for improved prevention and treatment.

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Spinal projecting neurons in rostral ventromedial medulla co-regulate motor and sympathetic tone

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CELL 2024年第13期187卷 3427-3444.e21页

作者： Zhang, Zicong Su, Junfeng Tang, Jing Chung, Leeyup Page, Jessica C. Winter, Carla C. Liu, Yuchu Kegeles, Evgenii Conti, Sara Zhang, Yu Biundo, Jason Chalif, Joshua I. Hua, Charles Y. Yang, Zhiyun Yao, Xue Yang, Yang Chen, Shuqiang Schwab, Jan M. Wang, Kuan Hong Chen, Chinfei Prerau, Michael J. He, Zhigang Boston Childrens Hosp FM Kirby Neurobiol Ctr Boston MA 02115 USA Harvard Med Sch Dept Neurol & Ophthalmol Boston MA 02115 USA Harvard Med Sch Harvard MIT MD PhD Program Boston MA USA Harvard Med Sch PhD Program Biol & Biomed Sci Boston MA USA Brigham & Womens Hosp Dept Neurosurg Boston MA USA Boston Univ Grad Program Neurosci Boston MA USA Ohio State Univ Belford Ctr Spinal Cord Injury Columbus OH USA Ohio State Univ Coll Med Dept Neurol & Neurosci Columbus OH USA Univ Rochester Med Ctr Dept Neurosci Rochester NY USA Brigham & Womens Hosp Div Sleep & Circadian Disorders Boston MA USA Harvard Med Sch Dept Med Boston MA USA

Many behaviors require the coordinated actions of somatic and autonomic functions. However, the underlying mechanisms remain elusive. By opto-stimulating different populations of descending spinal projecting neurons (SPNs) in anesthetized mice, we show that stimulation of excitatory SPNs in the rostral ventromedial medulla (rVMM) resulted in a simultaneous increase in somatomotor and sympathetic activities. Conversely, opto-stimulation of rVMM inhibitory SPNs decreased both activities. Anatomically, these SPNs innervate both sympathetic preganglionic neurons and motor-related regions in the spinal cord. Fiber-photometry recording indicated that the activities of rVMM SPNs correlate with different levels of muscle and sympathetic tone during distinct arousal states. Inhibiting rVMM excitatory SPNs reduced basal muscle and sympathetic tone, impairing locomotion initiation and high-speed performance. In contrast, silencing the inhibitory population abolished muscle atonia and sympathetic hypoactivity during rapid eye movement (REM) sleep. Together, these results identify rVMM SPNs as descending spinal projecting pathways controlling the tone of both the somatomotor and sympathetic systems.

关键词： spinal projecting neurons medulla motor control sympathetic regulation reticulospinal neurons blood pressure sympathetic tone

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The Genetics of Primary Microcephaly

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Genomics and Human Genetics 1000年第1期19卷 177-200页

作者： Divya Jayaraman Byoung-Il Bae Christopher A. Walsh 3Current affiliation: Boston Combined Residency Program (Child Neurology) Boston Children's Hospital Boston Massachusetts 02115 USA email: divya.jayaraman@childrens.harvard.edu 2Harvard-MIT MD-PhD Program Harvard Medical School Boston Massachusetts 02115 USA 1Division of Genetics and Genomics Manton Center for Orphan Disease Research and Howard Hughes Medical Institute Boston Children's Hospital Boston Massachusetts 02115 USA 4Department of Neurosurgery Yale University School of Medicine New Haven Connecticut 06510 USA email: byoung-il.bae@yale.edu 6Departments of Pediatrics and Neurology Harvard Medical School Boston Massachusetts 02115 USA email: christopher.walsh@childrens.harvard.edu 5Broad Institute of MIT and Harvard Cambridge Massachusetts 02142 USA

Primary microcephaly (MCPH, for “microcephaly primary hereditary”) is a disorder of brain development that results in a head circumference more than 3 standard deviations below the mean for age and gender. It has a wide variety of causes, including toxic exposures, in utero infections, and metabolic conditions. While the genetic microcephaly syndromes are relatively rare, studying these syndromes can reveal molecular mechanisms that are critical in the regulation of neural progenitor cells, brain size, and human brain evolution. Many of the causative genes for MCPH encode centrosomal proteins involved in centriole biogenesis. However, other MCPH genes fall under different mechanistic categories, notably DNA replication and repair. Recent gene discoveries and functional studies have implicated novel cellular processes, such as cytokinesis, centromere and kinetochore function, transmembrane or intracellular transport, Wnt signaling, and autophagy, as well as the apical polarity complex. Thus, MCPH genes implicate a wide variety of molecular and cellular mechanisms in the regulation of cerebral cortical size during development.

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Serological Markers of SARS-CoV-2 Reinfection

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MBIO 2022年第1期13卷 e0214121页

作者： Siddiqui, Sameed M. Bowman, Kathryn A. Zhu, Alex L. Fischinger, Stephanie Beger, Samuel Maron, Jenny S. Bartsch, Yannic C. Atyeo, Caroline Gorman, Matthew J. Yanis, Ahmad Hultquist, Judd F. Lorenzo-Redondo, Ramon Ozer, Egon A. Simons, Lacy M. Talj, Rana Rankin, Danielle A. Chapman, Lindsay Meade, Kyle Steinhart, Jordan Mullane, Sean Siebert, Suzanne Streeck, Hendrik Sabeti, Pardis Halasa, Natasha Musk, Elon R. Barouch, Dan H. Menon, Anil S. Nilles, Eric J. Lauffenburger, Douglas A. Alter, Galit MIT Computat & Syst Biol Program 77 Massachusetts Ave Cambridge MA 02139 USA Broad Inst MIT & Harvard Cambridge MA 02142 USA Ragon Inst MGH MIT & Harvard Cambridge MA 02139 USA Univ Duisburg Essen PhD Program Immunol & Virol Essen Germany Space Explorat Technol Corp Hawthorne CA USA Harvard Univ Div Med Sci PhD Program Virol Boston MA 02115 USA Vanderbilt Univ Med Ctr Dept Pediat Nashville TN 37232 USA Northwestern Univ Dept Med Feinberg Sch Med Div Infect Dis Chicago IL 60611 USA Northwestern Univ Ctr Pathogen Genom & Microbial Evolut Inst Global Hlth Feinberg Sch Med Chicago IL 60611 USA Vanderbilt Univ Sch Med Vanderbilt Epidemiol PhD Program Nashville TN 37212 USA Univ Bonn Univ Hosp Inst Virol Cologne Germany German Ctr Infect Res DZIF Partner Site Bonn Cologne Cologne Germany Harvard TH Chan Sch Publ Hlth Cambridge MA USA Howard Hughes Med Inst Chevy Chase MD USA Massachusetts Consortium Pathogen Readiness Boston MA 02115 USA Harvard Med Sch Beth Israel Deaconess Med Ctr Ctr Virol & Vaccine Res Boston MA 02115 USA Brigham & Womens Hosp Dept Emergency Med 75 Francis St Boston MA 02115 USA Harvard Univ Harvard Med Sch Cambridge MA 02138 USA Harvard Humanitarian Initiat Boston MA USA MIT Dept Biol Engn 77 Massachusetts Ave Cambridge MA 02139 USA

As public health guidelines throughout the world have relaxed in response to vaccination campaigns against SARS-CoV-2 it is likely that SARS-CoV-2 will remain endemic, fueled by the rise of more infectious SARS-CoV-2 variants. Moreover, in the setting of waning natural and vaccine immunity, reinfection have emerged across the globe, even among previously infected and vaccinated individuals. As such, the ability to detect reexposure to and reinfection by SARS-CoV-2 is a key component for global protection against this virus and, more importantly, against the potential emergence of vaccine escape mutations. Accordingly, there is a strong and continued need for the development and deployment of simple methods to detect emerging hot spots of reinfection to inform targeted pandemic response and containment, including targeted and specific deployment of vaccine booster campaigns. In this study, we identify simple, rapid immune biomarkers of reinfection in rhesus macaques, including lgG3 antibody levels against nucleocapsid and Fc gamma R2A receptor binding activity of anti-RBD antibodies, that are recapitulated in human reinfection cases. As such, this cross-species analysis underscores the potential utility of simple antibody titers and function as price-effective and scalable markers of reinfection to provide increased resolution and resilience against new outbreaks. IMPORTANCE As public health and social distancing guidelines loosen in the setting of waning global natural and vaccine immunity, a deeper understanding of the immunological response to reexposure and reinfection to this highly contagious pathogen is necessary to maintain public health. Viral sequencing analysis provides a robust but unrealistic means to monitor reinfection globally. The identification of scalable pathogen-specific biomarkers of reexposure and reinfection, however, could significantly accelerate our capacity to monitor the spread of the virus through naive and experienced hosts, providing k

关键词： SARS-CoV-2 reinfection antibodies humoral immunity diagnostics biomarkers

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Defining diurnal fluctuations in mouse choroid plexus and CSF at high molecular, spatial, and temporal resolution

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NATURE COMMUNICATIONS 2023年第1期14卷 3720页

作者： Fame, Ryann M. Kalugin, Peter N. Petrova, Boryana Xu, Huixin Soden, Paul A. Shipley, Frederick B. Dani, Neil Grant, Bradford Pragana, Aja Head, Joshua P. Gupta, Suhasini Shannon, Morgan L. Chifamba, Fortunate F. Hawks-Mayer, Hannah Vernon, Amanda Gao, Fan Zhang, Yong Holtzman, Michael J. Heiman, Myriam Andermann, Mark L. Kanarek, Naama Lipton, Jonathan O. Lehtinen, Maria K. Boston Childrens Hosp Dept Pathol Boston MA 02115 USA Harvard Med Sch Boston MA 02115 USA Harvard Med Sch Grad Program Neurosci Boston MA 02115 USA Harvard Med Sch Harvard MIT MD PhD Program Boston MA 02115 USA Harvard Univ Grad Program Biophys Cambridge MA 02138 USA Boston Childrens Hosp Dept Neurol Boston MA 02115 USA Boston Childrens Hosp FM Kirby Neurobiol Ctr Boston MA 02115 USA Harvard Med Sch Div Sleep Med Boston MA 02115 USA MIT Dept Brain & Cognit Sci Cambridge MA USA Picower Inst Learning & Memory Cambridge MA USA Broad Inst MIT & Harvard Cambridge MA 02142 USA Washington Univ Dept Med Pulm & Crit Care Med St Louis MO 63110 USA Beth Israel Deaconess Med Ctr Dept Med Div Endocrinol Diabet & Metab Boston MA 02115 USA Stanford Univ Dept Neurosurg Stanford CA 94305 USA Lyterian Therapeut San Francisco CA 94080 USA

Transmission and secretion of signals via the choroid plexus (ChP) brain barrier can modulate brain states via regulation of cerebrospinal fluid (CSF) composition. Here, we developed a platform to analyze diurnal variations in male mouse ChP and CSF. Ribosome profiling of ChP epithelial cells revealed diurnal translatome differences in metabolic machinery, secreted proteins, and barrier components. Using ChP and CSF metabolomics and blood-CSF barrier analyses, we observed diurnal changes in metabolites and cellular junctions. We then focused on transthyretin (TTR), a diurnally regulated thyroid hormone chaperone secreted by the ChP. Diurnal variation in ChP TTR depended on Bmal1 clock gene expression. We achieved real-time tracking of CSF-TTR in awake Ttr(mNeonGreen) mice via multi-day intracerebroventricular fiber photometry. Diurnal changes in ChP and CSF TTR levels correlated with CSF thyroid hormone levels. These datasets highlight an integrated platform for investigating diurnal control of brain states by the ChP and CSF.

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Schizophrenia risk from complex variation of complement component 4 (vol 530, pg 177, 2021)

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NATURE 2022年第7892期601卷 E4-E5页

作者： Sekar, Aswin Bialas, Allison R. de Rivera, Heather Davis, Avery Hammond, Timothy R. Kamitaki, Nolan Tooley, Katherine Presumey, Jessy Baum, Matthew Van Doren, Vanessa Genovese, Giulio Rose, Samuel A. Handsaker, Robert E. Daly, Mark J. Carroll, Michael C. Stevens, Beth McCarroll, Steven A. Department of Genetics Harvard Medical School Boston Massachusetts 02115 USA Stanley Center for Psychiatric Research Broad Institute of MIT and Harvard Cambridge Massachusetts 02142 USA MD-PhD Program Harvard Medical School Boston Massachusetts 02115 USA Department of Neurology F.M. Kirby Neurobiology Center Boston Children’s Hospital Harvard Medical School Boston Massachusetts 02115 USA Analytical and Translational Genetics Unit Massachusetts General Hospital Boston Massachusetts 02114 USA Program in Cellular and Molecular Medicine Boston Children’s Hospital Boston Massachusetts 02115 USA

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Metagenomic surveillance uncovers diverse and novel viral taxa in febrile patients from Nigeria

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NATURE COMMUNICATIONS 2023年第1期14卷 4693页

作者： Oguzie, Judith U. Petros, Brittany A. Oluniyi, Paul E. Mehta, Samar B. Eromon, Philomena E. Nair, Parvathy Adewale-Fasoro, Opeoluwa Ifoga, Peace Damilola Odia, Ikponmwosa Pastusiak, Andrzej Gbemisola, Otitoola Shobi Aiyepada, John Oke Uyigue, Eghosasere Anthonia Edamhande, Akhilomen Patience Blessing, Osiemi Airende, Michael Tomkins-Tinch, Christopher Qu, James Stenson, Liam Schaffner, Stephen F. Oyejide, Nicholas Ajayi, Nnenna A. Ojide, Kingsley Ogah, Onwe Abejegah, Chukwuyem Adedosu, Nelson Ayodeji, Oluwafemi Liasu, Ahmed A. Okogbenin, Sylvanus Okokhere, Peter O. Park, Daniel J. Folarin, Onikepe A. Komolafe, Isaac Ihekweazu, Chikwe Frost, Simon D. W. Jackson, Ethan K. Siddle, Katherine J. Sabeti, Pardis C. Happi, Christian T. Redeemers Univ Fac Nat Sci Dept Biol Sci Ede Osun State Nigeria Redeemers Univ African Ctr Excellence Genom Infect Dis ACEGID Ede Osun State Nigeria Broad Inst Harvard & MIT Cambridge MA 02142 USA Harvard MIT Program Hlth Sci & Technol Cambridge MA 02139 USA Harvard MIT MD PhD Program Boston MA 02115 USA Harvard Med Sch Dept Syst Biol Syst Synthet & Quantitat Biol PhD Program Boston MA 02115 USA Chan Zuckerberg Biohub San Francisco CA USA Univ Maryland Dept Med Med Ctr Baltimore MA USA Howard Hughes Med Inst Chevy Chase MD 20815 USA Irrua Specialist Teaching Hosp Irrua Edo State Nigeria Microsoft Premonit Redmond WA USA Harvard Univ Dept Organism & Evolutionary Biol Cambridge MA 02138 USA Alex Ekwueme Fed Univ Teaching Hosp Abakaliki Nigeria Fed Med Ctr Owo Ondo State Nigeria Nigeria Ctr Dis Control Abuja Nigeria London Sch Hyg & Trop Med London England Brown Univ Dept Mol Microbiol & Immunol Providence RI 02912 USA Harvard Univ Harvard TH Chan Sch Publ Hlth Dept Immunol & Infect Dis Boston MA 02115 USA

Effective infectious disease surveillance in high-risk regions is critical for clinical care and pandemic preemption;however, few clinical diagnostics are available for the wide range of potential human pathogens. Here, we conduct unbiased metagenomic sequencing of 593 samples from febrile Nigerian patients collected in three settings: i) population-level surveillance of individuals presenting with symptoms consistent with Lassa Fever (LF);ii) real-time investigations of outbreaks with suspected infectious etiologies;and iii) undiagnosed clinically challenging cases. We identify 13 distinct viruses, including the second and third documented cases of human blood-associated dicistrovirus, and a highly divergent, unclassified dicistrovirus that we name human blood-associated dicistrovirus 2. We show that pegivirus C is a common co-infection in individuals with LF and is associated with lower Lassa viral loads and favorable outcomes. We help uncover the causes of three outbreaks as yellow fever virus, monkeypox virus, and a noninfectious cause, the latter ultimately determined to be pesticide poisoning. We demonstrate that a local, Nigerian-driven metagenomics response to complex public health scenarios generates accurate, real-time differential diagnoses, yielding insights that inform policy. Applying metagenomics, the authors identify 13 viruses in febrile Nigerians, including a new dicistrovirus. Real-time phylogenetics spurred national vaccination campaigns, while retrospective analysis linked pegivirus C co-infections to favorable Lassa Fever outcomes.

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Characterization of Lineage Vs. Context-Dependent Essential Genes in Multiple Myeloma Using Crispr/Cas9 Genome Editing

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BLOOD 2016年第22期128卷 119-119页

作者： Matthews, Geoffrey M. Simoes, Ricardo De Matos Hu, Yiguo Sheffer, Michal Dhimolea, Eugen Hengeveld, Paul J. Bariteau, Megan A. Glassner, Brian Sievers, Quinlan Ebert, Benjamin L. Gandolfi, Sara Awate, Pallavi Tang, Huihui Vazquez, Franciska Culhane, Aedin mitsiades, Constantine S. Harvard Med Sch Dana Farber Canc Inst Dept Med Oncol Boston MA USA Univ Amsterdam Acad Med Ctr Dept Hematol Amsterdam Netherlands Broad Inst Harvard MIT MD PhD Program Cambridge MA USA Brigham & Womens Hosp Div Hematol Boston MA USA Univ Milan Milan Italy Humanitas Res Hosp Milan Italy Dana Farber Canc Inst Harvard Med Sch Dept Biostat & Computat Biol Boston MA USA

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Regulation of human cerebral cortical development by EXOC7 and EXOC8, components of the exocyst complex, and roles in neural progenitor cell proliferation and survival

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GENETICS IN MEDICINE 2020年第6期22卷 1040-1050页

作者： Coulter, Michael E. Musaev, Damir DeGennaro, Ellen M. Zhang, Xiaochang Henke, Katrin James, Kiely N. Smith, Richard S. Hill, R. Sean Partlow, Jennifer N. Muna Al-Saffar Kamumbu, A. Stacy Hatem, Nicole Barkovich, A. James Aziza, Jacqueline Chassaing, Nicolas Zaki, Maha S. Sultan, Tipu Burglen, Lydie Rajab, Anna Al-Gazali, Lihadh Mochida, Ganeshwaran H. Harris, Matthew P. Gleeson, Joseph G. Walsh, Christopher A. Harvard Med Sch Div Genet & Genom Boston MA 02115 USA Harvard Med Sch Howard Hughes Med Inst Boston Childrens Hosp Dept Pediat Boston MA 02115 USA Harvard Med Sch Howard Hughes Med Inst Boston Childrens Hosp Dept Neurol Boston MA 02115 USA Harvard Med Sch Program Neurosci Boston MA 02115 USA Harvard Med Sch Harvard MIT MD PHD Program Boston MA 02115 USA Univ San Diego Dept Neurosci La Jolla CA 92110 USA Univ San Diego Howard Hughes Med Inst La Jolla CA 92110 USA MIT Harvard Mit Div Hlth Sci & Technol Cambridge MA 02139 USA Univ Chicago Dept Human Genet Chicago IL 60637 USA Harvard Med Sch Boston Childrens Hosp Dept Genet Div Orthoped Res Boston MA 02115 USA United Arab Emirates Univ Coll Med & Hlth Sci Dept Paediat Al Ain U Arab Emirates Univ Calif San Francisco Dept Radiol Benioff Childrens Hosp San Francisco CA USA Univ Calif San Francisco Dept Pediat Benioff Childrens Hosp San Francisco CA USA Univ Calif San Francisco Dept Neurol Benioff Childrens Hosp San Francisco CA USA Univ Calif San Francisco Dept Neurol Surg Benioff Childrens Hosp San Francisco CA USA CHU Toulouse Inst Univ Canc Toulouse Oncopole Dept Pathol Toulouse France CHU Toulouse Serv Genet Med Toulouse France Univ Toulouse UDEAR INSERM UMR 1056 Toulouse France Natl Res Ctr Human Genet & Genome Res Div Dept Clin Genet Cairo Egypt Inst Child Hlth Dept Pediat Neurol Lahore Pakistan Childrens Hosp Lahore Pakistan Sorbonne Univ Ctr Reference Malformat & Malad Congenitales Cerv Dept Genet AP HP Paris France Hop Trousseau Paris France INSERM Dev Brain Disorders Lab Imagine Inst UMR 1163 Paris France Minist Hlth Directorate Gen Hlth Affairs Natl Genet Ctr Muscat Oman Massachusetts Gen Hosp Dept Neurol Boston MA 02114 USA

Purpose The exocyst complex is a conserved protein complex that mediates fusion of intracellular vesicles to the plasma membrane and is implicated in processes including cell polarity, cell migration, ciliogenesis, cytokinesis, autophagy, and fusion of secretory vesicles. The essential role of these genes in human genetic disorders, however, is unknown. Methods We performed homozygosity mapping and exome sequencing of consanguineous families with recessively inherited brain development disorders. We modeled an EXOC7 splice variant in vitro and examined EXOC7 messenger RNA (mRNA) expression in developing mouse and human cortex. We modeled exoc7 loss-of-function in a zebrafish knockout. Results We report variants in exocyst complex members, EXOC7 and EXOC8, in a novel disorder of cerebral cortex development. In EXOC7, we identified four independent partial loss-of-function (LOF) variants in a recessively inherited disorder characterized by brain atrophy, seizures, and developmental delay, and in severe cases, microcephaly and infantile death. In EXOC8, we found a homozygous truncating variant in a family with a similar clinical disorder. We modeled exoc7 deficiency in zebrafish and found the absence of exoc7 causes microcephaly. Conclusion Our results highlight the essential role of the exocyst pathway in normal cortical development and how its perturbation causes complex brain disorders.

关键词： exocyst EXOC7 EXOC8 microcephaly developmental delay

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