Hope Center member publications

List of publications for the week of August 30, 2021

Nicotinic acid mononucleotide is an allosteric SARM1 inhibitor promoting axonal protection” (2021) Experimental Neurology

Nicotinic acid mononucleotide is an allosteric SARM1 inhibitor promoting axonal protection
(2021) Experimental Neurology, 345, art. no. 113842, . 

Sasaki, Y.a e , Zhu, J.a e , Shi, Y.b , Gu, W.c , Kobe, B.c , Ve, T.b , DiAntonio, A.d e e , Milbrandt, J.a e e

a Washington University School of Medicine in Saint Louis, Department of Genetics, St. Louis, MO, United States
b Institute for Glycomics, Griffith University, Southport, QLD 4222, Australia
c School of Chemistry and Molecular Biosciences, Institute for Molecular Bioscience and Australian Infectious Diseases Research Centre, University of QueenslandQLD 4072, Australia
d Washington University School of Medicine in Saint Louis, Department of Developmental Biology, St. Louis, MO, United States
e Needleman Center for Neurometabolism and Axonal Therapeutics, United States

SARM1 is an inducible NAD+ hydrolase that is the central executioner of pathological axon loss. Recently, we elucidated the molecular mechanism of SARM1 activation, demonstrating that SARM1 is a metabolic sensor regulated by the levels of NAD+ and its precursor, nicotinamide mononucleotide (NMN), via their competitive binding to an allosteric site within the SARM1 N-terminal ARM domain. In healthy neurons with abundant NAD+, binding of NAD+ blocks access of NMN to this allosteric site. However, with injury or disease the levels of the NAD+ biosynthetic enzyme NMNAT2 drop, increasing the NMN/ NAD+ ratio and thereby promoting NMN binding to the SARM1 allosteric site, which in turn induces a conformational change activating the SARM1 NAD+ hydrolase. Hence, NAD+ metabolites both regulate the activation of SARM1 and, in turn, are regulated by the SARM1 NAD+ hydrolase. This dual upstream and downstream role for NAD+ metabolites in SARM1 function has hindered mechanistic understanding of axoprotective mechanisms that manipulate the NAD+ metabolome. Here we reevaluate two methods that potently block axon degeneration via modulation of NAD+ related metabolites, 1) the administration of the NMN biosynthesis inhibitor FK866 in conjunction with the NAD+ precursor nicotinic acid riboside (NaR) and 2) the neuronal expression of the bacterial enzyme NMN deamidase. We find that these approaches not only lead to a decrease in the levels of the SARM1 activator NMN, but also an increase in the levels of the NAD+ precursor nicotinic acid mononucleotide (NaMN). We show that NaMN inhibits SARM1 activation, and demonstrate that this NaMN-mediated inhibition is important for the long-term axon protection induced by these treatments. Analysis of the NaMN-ARM domain co-crystal structure shows that NaMN competes with NMN for binding to the SARM1 allosteric site and promotes the open, autoinhibited configuration of SARM1 ARM domain. Together, these results demonstrate that the SARM1 allosteric pocket can bind a diverse set of metabolites including NMN, NAD+, and NaMN to monitor cellular NAD+ homeostasis and regulate SARM1 NAD+ hydrolase activity. The relative promiscuity of the allosteric site may enable the development of potent pharmacological inhibitors of SARM1 activation for the treatment of neurodegenerative disorders. © 2021 Elsevier Inc.

Author Keywords
crystallography;  mass spectrometer;  NADase;  NAMPT;  Neuropathy;  NMR;  TIR;  Traumatic brain injury;  Vitamin;  Wallerian degeneration;  X-ray

Funding details
National Institutes of HealthNIHR01CA219866, RF1AG013730, RO1NS087632
Australian Research CouncilARCFL180100109, FT200100572
National Health and Medical Research CouncilNHMRC1071659, 1107804, 1160570, 1196590

Document Type: Article
Publication Stage: Final
Source: Scopus

ELAVL4, splicing, and glutamatergic dysfunction precede neuron loss in MAPT mutation cerebral organoids” (2021) Cell

ELAVL4, splicing, and glutamatergic dysfunction precede neuron loss in MAPT mutation cerebral organoids
(2021) Cell, 184 (17), pp. 4547-4563.e17. Cited 1 time.

Bowles, K.R.a , Silva, M.C.b , Whitney, K.a c , Bertucci, T.d , Berlind, J.E.e , Lai, J.D.e f , Garza, J.C.b , Boles, N.C.d , Mahali, S.g , Strang, K.H.a c , Marsh, J.A.g , Chen, C.g , Pugh, D.A.a , Liu, Y.a , Gordon, R.E.c , Goderie, S.K.d , Chowdhury, R.d , Lotz, S.d , Lane, K.d , Crary, J.F.c , Haggarty, S.J.b , Karch, C.M.g , Ichida, J.K.e , Goate, A.M.a , Temple, S.d

a Ronald M. Loeb Center for Alzheimer’s Disease, Friedman Brain Institute, Departments of Genetics and Genomic Sciences, Neuroscience, and Neurology, Icahn School of Medicine at Mount Sinai (ISMMS), New York, NY 10029, United States
b Chemical Neurobiology Laboratory, Center for Genomic Medicine, Departments of Neurology and Psychiatry, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, United States
c Department of Pathology, Neuropathology Brain Bank and Research Core, ISMMS, New York, NY 10029, United States
d Neural Stem Cell Institute, Rensselaer, NY 12144, United States
e Department of Stem Cell Biology and Regenerative Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, United States
f Amgen Research, One Amgen Center Dr., Thousand Oaks, CA 91320, United States
g Department of Psychiatry, Washington University in St. Louis, St. Louis, MO 63110, United States

Frontotemporal dementia (FTD) because of MAPT mutation causes pathological accumulation of tau and glutamatergic cortical neuronal death by unknown mechanisms. We used human induced pluripotent stem cell (iPSC)-derived cerebral organoids expressing tau-V337M and isogenic corrected controls to discover early alterations because of the mutation that precede neurodegeneration. At 2 months, mutant organoids show upregulated expression of MAPT, glutamatergic signaling pathways, and regulators, including the RNA-binding protein ELAVL4, and increased stress granules. Over the following 4 months, mutant organoids accumulate splicing changes, disruption of autophagy function, and build-up of tau and P-tau-S396. By 6 months, tau-V337M organoids show specific loss of glutamatergic neurons as seen in individuals with FTD. Mutant neurons are susceptible to glutamate toxicity, which can be rescued pharmacologically by the PIKFYVE kinase inhibitor apilimod. Our results demonstrate a sequence of events that precede neurodegeneration, revealing molecular pathways associated with glutamate signaling as potential targets for therapeutic intervention in FTD. © 2021

Author Keywords
autophagy;  ELAVL4;  frontotemporal dementia;  glutamatergic neurons;  MAPT;  organoids;  splicing;  synaptic signaling;  tauopathy

Funding details
NS110890, R01AG054008, R01NS095252
National Institutes of HealthNIHAG046374
U.S. Department of DefenseDODW81XWH-20-1-0424, W81XWH-21-1-0131, W81XWH-21-1-0168
National Institute on AgingNIA2R01NS097850, R01 AG056293
National Institute of Neurological Disorders and StrokeNINDSF31NS117075, R35 NS097277
California Institute for Regenerative MedicineCIRM
ALS AssociationALSA
Alzheimer’s Drug Discovery FoundationADDF
New York Stem Cell FoundationNYSCF
Association for Frontotemporal DegenerationAFTD
BrightFocus FoundationBFF
New York State Stem Cell ScienceNYSTEMC029158
Hope Center for Neurological Disorders
New York Genome CenterNYGCU01AG045390, U54NS092089
Rainwater Charitable FoundationRCF
Tau Consortium
Denali Therapeutics
Sächsische AufbaubankSAB

Document Type: Article
Publication Stage: Final
Source: Scopus

Accelerating Prediction of Malignant Cerebral Edema After Ischemic Stroke with Automated Image Analysis and Explainable Neural Networks” (2021) Neurocritical Care

Accelerating Prediction of Malignant Cerebral Edema After Ischemic Stroke with Automated Image Analysis and Explainable Neural Networks
(2021) Neurocritical Care, . 

Foroushani, H.M.a , Hamzehloo, A.b , Kumar, A.b , Chen, Y.b , Heitsch, L.c , Slowik, A.d , Strbian, D.e , Lee, J.-M.b , Marcus, D.S.f , Dhar, R.b

a Department of Electrical and Systems Engineering, Washington University in St. Louis McKelvey School of Engineering, 1 Brookings Drive, 63130-4899, St. Louis, MO, United States
b Department of Neurology, Washington University in St. Louis School of Medicine, 660 S Euclid Avenue, Campus, Box 8111, St. Louis, MO 63110, United States
c Department of Emergency Medicine, Washington University in St. Louis School of Medicine, 660 S. Euclid Ave, Campus, Box 8072, St. Louis, MO 63110, United States
d Department of Neurology, Jagiellonian University Medical College, Kraków, Poland
e Department of Neurology, Helsinki University Hospital, Helsinki, Finland
f Department of Radiology, Washington University in St. Louis School of Medicine, 525 Scott Ave, Campus, Box 8225, St. Louis, MO 63110, United States

Background: Malignant cerebral edema is a devastating complication of stroke, resulting in deterioration and death if hemicraniectomy is not performed prior to herniation. Current approaches for predicting this relatively rare complication often require advanced imaging and still suffer from suboptimal performance. We performed a pilot study to evaluate whether neural networks incorporating data extracted from routine computed tomography (CT) imaging could enhance prediction of edema in a large diverse stroke cohort. Methods: An automated imaging pipeline retrospectively extracted volumetric data, including cerebrospinal fluid (CSF) volumes and the hemispheric CSF volume ratio, from baseline and 24 h CT scans performed in participants of an international stroke cohort study. Fully connected and long short-term memory (LSTM) neural networks were trained using serial clinical and imaging data to predict those who would require hemicraniectomy or die with midline shift. The performance of these models was tested, in comparison with regression models and the Enhanced Detection of Edema in Malignant Anterior Circulation Stroke (EDEMA) score, using cross-validation to construct precision-recall curves. Results: Twenty of 598 patients developed malignant edema (12 required surgery, 8 died). The regression model provided 95% recall but only 32% precision (area under the precision-recall curve [AUPRC] 0.74), similar to the EDEMA score (precision 28%, AUPRC 0.66). The fully connected network did not perform better (precision 33%, AUPRC 0.71), but the LSTM model provided 100% recall and 87% precision (AUPRC 0.97) in the overall cohort and the subgroup with a National Institutes of Health Stroke Scale (NIHSS) score ≥ 8 (p = 0.0001 vs. regression and fully connected models). Features providing the most predictive importance were the hemispheric CSF ratio and NIHSS score measured at 24 h. Conclusions: An LSTM neural network incorporating volumetric data extracted from routine CT scans identified all cases of malignant cerebral edema by 24 h after stroke, with significantly fewer false positives than a fully connected neural network, regression model, and the validated EDEMA score. This preliminary work requires prospective validation but provides proof of principle that a deep learning framework could assist in selecting patients for surgery prior to deterioration. © 2021, Springer Science+Business Media, LLC, part of Springer Nature and Neurocritical Care Society.

Author Keywords
Brain computed tomography scan;  Brain edema;  Cerebral infarction;  Deep learning;  Early diagnosis

Funding details
National Institutes of HealthNIHK23NS099440, K23NS099487, P30NS098577, R01NS085419

Document Type: Article
Publication Stage: Article in Press
Source: Scopus

Subgroup and subtype-specific outcomes in adult medulloblastoma” (2021) Acta Neuropathologica

Subgroup and subtype-specific outcomes in adult medulloblastoma
(2021) Acta Neuropathologica, . 

Coltin, H.a b , Sundaresan, L.b , Smith, K.S.c , Skowron, P.b , Massimi, L.d , Eberhart, C.G.e , Schreck, K.C.f , Gupta, N.g , Weiss, W.A.h , Tirapelli, D.i , Carlotti, C.i , Li, K.K.W.j , Ryzhova, M.k , Golanov, A.k , Zheludkova, O.k , Absalyamova, O.k , Okonechnikov, K.l , Stichel, D.m , von Deimling, A.m , Giannini, C.n , Raskin, S.o , Van Meir, E.G.p , Chan, J.A.q , Fults, D.r , Chambless, L.B.s , Kim, S.-K.t , Vasiljevic, A.u v , Faure-Conter, C.w , Vibhakar, R.x , Jung, S.y , Leary, S.z , Mora, J.aa , McLendon, R.E.ab , Pollack, , Hauser, , Grajkowska, , Rubin, , van Veelen, , French, P.J.ah , Kros, , Liau, L.M.aj , Pfister, S.M.l ak , Kool, M.l al , Kijima, , Taylor, M.D.b , Packer, R.J.o , Northcott, P.A.c , Korshunov, A.m , Ramaswamy, V.a b an

a Division of Haematology/Oncology, Hospital for Sick Children, 555 University Avenue, Toronto, ON, Canada
b Programme in Developmental and Stem Cell Biology, Arthur and Sonia Labatt Brain Tumour Research Centre, Hospital for Sick Children, Toronto, ON, Canada
c Department of Developmental Neurobiology, St. Jude Children’s Research Hospital, MS 325, Room D2058, 262 Danny Thomas Place, Memphis, TN 38105-3678, United States
d Department of Neurosurgery, Fondazione Policlinico A. Gemelli IRCCS, Catholic University Medical School, Rome, Italy
e Department of Neuropathology and Ophthalmic Pathology, Johns Hopkins University, Baltimore, MD, United States
f Department of Neurology, Johns Hopkins University, Baltimore, MD, United States
g Departments of Neurological Surgery and Pediatrics, University of California, San Francisco, CA, United States
h Departments of Neurology, Neurological Surgery, and Pediatrics, University of California, San Francisco, CA, United States
i Department of Surgery and Anatomy, Faculty of Medicine of Ribeirão Preto, University of Sao Paulo, São Paulo, Brazil
j Department of Anatomical and Cellular Pathology, The Chinese University of Hong Kong, Shatin, New Territories, Hong Kong
k NN Burdenko Neurosurgical Research Centre, Moscow, Russian Federation
l Hopp Children’s Cancer Center Heidelberg (KiTZ) and Division of Pediatric Neurooncology, German Cancer Research Center (DKFZ), Heidelberg, Germany
m Clinical Cooperation Unit Neuropathology (B300), German Cancer Research Center (DKFZ) and Department of Neuropathology, University of Heidelberg, University Hospital Heidelberg, Im Neuenheimer Feld 224, Heidelberg, 69120, Germany
n Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, United States
o Center for Cancer and Blood Disorders, Children’s National Medical Center, Washington, DC, United States
p Department of Neurosurgery, O’Neal Comprehensive Cancer Center, University of Alabama at Birmingham (UAB), Birmingham, AL, United States
q Department of Pathology and Laboratory Medicine, University of Calgary, Calgary, AB, Canada
r Department of Neurosurgery, University of Utah, Salt Lake City, UT, United States
s Department of Neurological Surgery, Vanderbilt Medical Center, Nashville, TN, United States
t Department of Neurosurgery, Division of Pediatric Neurosurgery, Seoul National University Children’s Hospital, Seoul, South Korea
u Centre de Pathologie et Neuropathologie Est, Centre de Biologie et Pathologie Est, Groupement Hospitalier Est, Hospices Civils de Lyon, Bron, France
v ONCOFLAM, Neuro-Oncologie Et Neuro-Inflammation Centre de Recherche en Neurosciences de Lyon, Lyon, France
w Department of Pediatrics, Institut d’Hemato-Oncologie Pediatrique, Lyon, France
x Department of Pediatrics, University of Colorado Denver, Aurora, CO, United States
y Department of Neurosurgery, Chonnam National University Research Institute of Medical Sciences, Chonnam National University Hwasun Hospital and Medical School, Hwasun-gun, Chonnam, South Korea
z Cancer and Blood Disorders Center, Seattle Children’s Hospital, Seattle, WA, United States
aa Developmental Tumor Biology Laboratory, Hospital Sant Joan de Déu, Esplugues de Llobregat, Barcelona, Spain
ab Department of Pathology, Duke University, Durham, NC, United States
ac Department of Neurological Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA, United States
ad 2nd Department of Pediatrics, Semmelweis University, Budapest, Hungary
ae Department of Pathology, The Children’s Memorial Health Institute, Warsaw, Poland
af Departments of Pediatrics, Anatomy and Neurobiology, Washington University School of Medicine and St Louis Children’s Hospital, St Louis, MO, United States
ag Department of Neurosurgery, Brain Tumour Center, Erasmus MC Cancer Institute, Rotterdam, Netherlands
ah Department of Neurology, Brain Tumour Center, Erasmus MC Cancer Institute, Rotterdam, Netherlands
ai Department of Pathology, Erasmus University Medical Center, Rotterdam, Netherlands
aj Department of Neurosurgery, David Geffen School of Medicine at University of California at Los Angeles, University of California Los Angeles, Los Angeles, CA 90095, United States
ak Department of Pediatric Oncology, Hematology and Immunology, University of Heidelberg, Heidelberg, Germany
al Princess Máxima Center for Pediatric Oncology, Utrecht, Netherlands
am Department of Neurosurgery, Osaka University Graduate School of Medicine, Suita, Japan
an Department of Medical Biophysics, University of Toronto, Toronto, ON, Canada

Medulloblastoma, a common pediatric malignant central nervous system tumour, represent a small proportion of brain tumours in adults. Previously it has been shown that in adults, Sonic Hedgehog (SHH)-activated tumours predominate, with Wingless-type (WNT) and Group 4 being less common, but molecular risk stratification remains a challenge. We performed an integrated analysis consisting of genome-wide methylation profiling, copy number profiling, somatic nucleotide variants and correlation of clinical variables across a cohort of 191 adult medulloblastoma cases identified through the Medulloblastoma Advanced Genomics International Consortium. We identified 30 WNT, 112 SHH, 6 Group 3, and 41 Group 4 tumours. Patients with SHH tumours were significantly older at diagnosis compared to other subgroups (p < 0.0001). Five-year progression-free survival (PFS) for WNT, SHH, Group 3, and Group 4 tumours was 64.4 (48.0–86.5), 61.9% (51.6–74.2), 80.0% (95% CI 51.6–100.0), and 44.9% (95% CI 28.6–70.7), respectively (p = 0.06). None of the clinical variables (age, sex, metastatic status, extent of resection, chemotherapy, radiotherapy) were associated with subgroup-specific PFS. Survival among patients with SHH tumours was significantly worse for cases with chromosome 3p loss (HR 2.9, 95% CI 1.1–7.6; p = 0.02), chromosome 10q loss (HR 4.6, 95% CI 2.3–9.4; p < 0.0001), chromosome 17p loss (HR 2.3, 95% CI 1.1–4.8; p = 0.02), and PTCH1 mutations (HR 2.6, 95% CI 1.1–6.2; p = 0.04). The prognostic significance of 3p loss and 10q loss persisted in multivariable regression models. For Group 4 tumours, chromosome 8 loss was strongly associated with improved survival, which was validated in a non-overlapping cohort (combined cohort HR 0.2, 95% CI 0.1–0.7; p = 0.007). Unlike in pediatric medulloblastoma, whole chromosome 11 loss in Group 4 and chromosome 14q loss in SHH was not associated with improved survival, where MYCN, GLI2 and MYC amplification were rare. In sum, we report unique subgroup-specific cytogenetic features of adult medulloblastoma, which are distinct from those in younger patients, and correlate with survival disparities. Our findings suggest that clinical trials that incorporate new strategies tailored to high-risk adult medulloblastoma patients are urgently needed. © 2021, The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.

Author Keywords
Adult;  DNA methylation profiling;  Medulloblastoma;  Molecular groups;  Risk stratification

Funding details
National Institutes of HealthNIH5R01CA159859-08, R01CA235162, R01NS096236, R01NS106155-01
Pediatric Brain Tumor FoundationPBTF
Stand Up To CancerSU2CSU2C-AACR-DT1113
Princess Margaret Cancer FoundationPMCF
Government of Ontario
Canadian Cancer Society Research InstituteCCSRI
Canadian Institutes of Health ResearchCIHR
Ontario Ministry of Research, Innovation and ScienceMRIS
Garron Family Cancer CentreGFCC

Document Type: Article
Publication Stage: Article in Press
Source: Scopus

Biallelic loss-of-function variants in the splicing regulator NSRP1 cause a severe neurodevelopmental disorder with spastic cerebral palsy and epilepsy” (2021) Genetics in Medicine

Biallelic loss-of-function variants in the splicing regulator NSRP1 cause a severe neurodevelopmental disorder with spastic cerebral palsy and epilepsy
(2021) Genetics in Medicine, . 

Calame, D.G.a b c , Bakhtiari, S.d e , Logan, R.f , Coban-Akdemir, Z.c g , Du, H.c , Mitani, T.c , Fatih, J.M.c , Hunter, J.V.h i , Herman, I.a b c , Pehlivan, D.a b c , Jhangiani, S.N.j , Person, R.k , Schnur, R.E.k , Jin, S.C.l , Bilguvar, K.m , Posey, J.E.c , Koh, S.n , Firouzabadi, S.G.o , Alehabib, E.p , Tafakhori, A.q , Esmkhani, S.r , Gibbs, R.A.c j , Noureldeen, M.M.s , Zaki, M.S.t , Marafi, D.c u , Darvish, H.v , Kruer, M.C.d e , Lupski, J.R.b c j w

a Division of Neurology and Developmental Neuroscience, Department of Pediatrics, Baylor College of Medicine, Houston, TX, United States
b Texas Children’s Hospital, Houston, TX, United States
c Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, United States
d Pediatric Movement Disorders Program, Division of Pediatric Neurology, Barrow Neurological Institute, Phoenix Children’s Hospital, Phoenix, AZ, United States
e Departments of Child Health, Neurology, and Cellular & Molecular Medicine, and Program in Genetics, University of Arizona College of Medicine–Phoenix, Phoenix, AZ, United States
f Division of Neurosciences, Children’s Healthcare of Atlanta, Atlanta, GA, United States
g Human Genetics Center, Department of Epidemiology, Human Genetics, and Environmental Sciences, School of Public Health, The University of Texas Health Science Center at Houston, Houston, TX, United States
h Department of Radiology, Baylor College of Medicine, Houston, TX, United States
i E.B. Singleton Department of Pediatric Radiology, Texas Children’s Hospital, Houston, TX, United States
j Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX, United States
k GeneDX, Gaithersburg, MD, United States
l Department of Genetics, Washington University School of Medicine, St. Louis, MO, United States
m Department of Genetics, Yale University, New Haven, CT, United States
n Department of Pediatrics, Children’s Hospital, University of Nebraska, Omaha, NE, United States
o Genetics Research Center, University of Social Welfare and Rehabilitation Sciences, Tehran, Iran
p Student Research Committee, Department of Medical Genetics, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
q Iranian Center of Neurological Research, Neuroscience Institute, Tehran University of Medical Sciences, Tehran, Iran
r Department of Basic Oncology, Division of Cancer Genetics, Oncology Institute, Istanbul University, Istanbul, Turkey
s Department of Pediatrics, Faculty of Medicine, Beni-Suef University, Beni-Suef, Egypt
t Department of Clinical Genetics, Human Genetics and Genome Research Division, National Research Centre, Cairo, Egypt
u Department of Pediatrics, Faculty of Medicine, Kuwait University, Safat, Kuwait
v Neuroscience Research Center, Faculty of Medicine, Golestan University of Medical Sciences, Gorgan, Iran
w Department of Pediatrics, Baylor College of Medicine, Houston, TX, United States

Purpose: Alternative splicing plays a critical role in mouse neurodevelopment, regulating neurogenesis, cortical lamination, and synaptogenesis, yet few human neurodevelopmental disorders are known to result from pathogenic variation in splicing regulator genes. Nuclear Speckle Splicing Regulator Protein 1 (NSRP1) is a ubiquitously expressed splicing regulator not known to underlie a Mendelian disorder. Methods: Exome sequencing and rare variant family-based genomics was performed as a part of the Baylor-Hopkins Center for Mendelian Genomics Initiative. Additional families were identified via GeneMatcher. Results: We identified six patients from three unrelated families with homozygous loss-of-function variants in NSRP1. Clinical features include developmental delay, epilepsy, variable microcephaly (Z-scores −0.95 to −5.60), hypotonia, and spastic cerebral palsy. Brain abnormalities included simplified gyral pattern, underopercularization, and/or vermian hypoplasia. Molecular analysis identified three pathogenic NSRP1 predicted loss-of-function variant alleles: c.1359_1362delAAAG (p.Glu455AlafsTer20), c.1272dupG (p.Lys425GlufsTer5), and c.52C>T (p.Gln18Ter). The two frameshift variants result in a premature termination codon in the last exon, and the mutant transcripts are predicted to escape nonsense mediated decay and cause loss of a C-terminal nuclear localization signal required for NSRP1 function. Conclusion: We establish NSRP1 as a gene for a severe autosomal recessive neurodevelopmental disease trait characterized by developmental delay, epilepsy, microcephaly, and spastic cerebral palsy. © 2021, The Author(s), under exclusive licence to the American College of Medical Genetics and Genomics.

Funding details
U54 HG006504-01
National Institutes of HealthNIH873841, T32 GM007526-42, T32 NS043124-19
National Heart, Lung, and Blood InstituteNHLBI
National Human Genome Research InstituteNHGRI
National Institute of Neurological Disorders and StrokeNINDSR01NS106298, R35NS105078
International Rett Syndrome FoundationIRSF3701‐1, K08 HG008986
Muscular Dystrophy AssociationMDA512848
Uehara Memorial Foundation
Cerebral Palsy Alliance Research FoundationCPARF01318
Baylor-Hopkins Center for Mendelian GenomicsBHCMGUM1 HG006542
Spastic Paraplegia FoundationSPF

Document Type: Article
Publication Stage: Article in Press
Source: Scopus