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Papers Published in 2021

Title: APC7 mediates ubiquitin signaling in constitutive heterochromatin in the developing mammalian brain Published: December 22, 2021 Publication: Molecular Cell

Authors: Cole J. Ferguson, Olivia Urso, Tatyana Bodrug, Brandon M. Gassaway, Edmond R. Watson, Jesuraj R. Prabu, Pablo Lara-Gonzalez, Raquel C. Martinez-Chacin, Dennis Y. Wu, Karlla W. Brigatti, Erik G. Puffenberger, Cora M. Taylor, Barbara Haas-Givler, Robert N. Jinks, Kevin A. Strauss, Arshad Desai, Harrison W. Gabel, Steven P. Gygi, Brenda A. Schulman, Nicholas G. Brown, Azad Bonni

Abstract:
Neurodevelopmental cognitive disorders provide insights into mechanisms of human brain development. Here, we report an intellectual disability syndrome caused by the loss of APC7, a core component of the E3 ubiquitin ligase anaphase promoting complex (APC). In mechanistic studies, we uncover a critical role for APC7 during the recruitment and ubiquitination of APC substrates. In proteomics analyses of the brain from mice harboring the patient-specific APC7 mutation, we identify the chromatin-associated protein Ki-67 as an APC7-dependent substrate of the APC in neurons. Conditional knockout of the APC coactivator protein Cdh1, but not Cdc20, leads to the accumulation of Ki-67 protein in neurons in vivo, suggesting that APC7 is required for the function of Cdh1-APC in the brain. Deregulated neuronal Ki-67 upon APC7 loss localizes predominantly to constitutive heterochromatin. Our findings define an essential function for APC7 and Cdh1-APC in neuronal heterochromatin regulation, with implications for understanding human brain development and disease.
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Title: Long-term liver transplant outcomes for progressive familial intrahepatic cholestasis type 1: The Pittsburgh experience Published: December 1, 2021 Publication: Pediatric Transplantation

Authors: Sarah A F Henkel, Claudia M Salgado, Miguel Reyes-Mugica, Kyle A Soltys, Kevin Strauss, George V Mazariegos, Robert H Squires, Patrick J McKiernan, Xingyu Zhang, James E Squires

Abstract:
Background: Progressive familial intrahepatic cholestasis type 1 (PFIC1) arises from biallelic variants in the ATP8B1 gene that annul FIC1 activity, resulting in progressive liver disease. Liver transplant (LT) is indicated in refractory disease; however, post-LT complications including worsening diarrhea and steatohepatitis progressing to fibrosis with graft loss have been reported. We aim to describe long-term outcomes of PFIC1 LT recipients at our center, focusing on the histological changes of the allografts. Methods: We assessed 7 PFIC1 patients post-LT at the Children's Hospital of Pittsburgh (CHP). All pre-transplant, explant, and sequential post-transplant pathology samples were reviewed. Continuous data are presented as the mean ± SD. We compared the pre- and post-transplant height and weight z-scores using Wilcoxon signed-rank test. Results: Seven (29% male) patients with PFIC1 received a LT (n = 6) or had post-LT care (n = 1) at CHP. Six had confirmed or suspected identical genetic. At a mean follow-up of 10.9 years, both patient survival and graft survival were 100%. Diarrhea persisted (n = 3) or newly developed (n = 4) in all patients after LT contributing to ongoing growth failure, with mean z-scores -2.63 (weight) and -2.98 (height) at follow-up. Histologically, allograft steatosis was common but was not accompanied by significant inflammation, ballooning, or fibrosis. Conclusion: We show that extrahepatic disease persists and near-universal allograft steatosis occurs. However, at a mean follow-up period of over 10 years, no patients developed steatohepatitis or significant fibrosis, and both patient survival and graft survival are excellent.
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Title: Mendelian disease research in the Plain populations of Lancaster County, Pennsylvania Published: November 10, 2021 Publication: American Journal of Medical Genetics Part A

Authors: Erik G. Puffenberger

Abstract:

Founder populations have long contributed to our knowledge of rare disease genes and phenotypes. From the pioneering work of Dr. Victor McKusick to today, research in these groups has shed light on rare recessive phenotypes, expanded the clinical spectrum of disease, and facilitated disease gene identification. Current clinical and research studies in these special groups augment the wealth of knowledge already gained, provide new insights into emerging problems such as variant interpretation and reduced penetrance, and contribute to the development of novel therapies for rare genetic diseases. Clinical developments over the past 30 years have altered the fundamental relationship with the Lancaster Plain communities: research has become more collaborative, and the knowledge imparted by these studies is now being harnessed to provide cutting-edge translational medicine to the very community of vulnerable individuals who need it most.

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Title: Nusinersen by subcutaneous intrathecal catheter for symptomatic spinal muscular atrophy patients with complex spine anatomy Published: October 20, 2021 Publication: Muscle & Nerve

Authors: Vincent J. Carson MD, Millie Young RNC, Karlla W. Brigatti MS, CGC, Donna L. Robinson, CRNP, Robert M. Reed MD, Jihee Sohn PhD, Marco Petrillo PhD, Wildon Farwell MD, PhD, Freeman Miller MD, Kevin A. Strauss MD

Abstract:
Introduction/Aims: Intrathecal administration of nusinersen is challenging in patients with spinal muscular atrophy (SMA) who have spine deformities or fusions. We prospectively studied the safety and efficacy of nusinersen administration via an indwelling subcutaneous intrathecal catheter (SIC) for SMA patients with advanced disease. Methods: Seventeen participants commenced nusinersen therapy between 2.7 and 31.5 years of age and received 9 to 12 doses via SIC. Safety was assessed in all participants. A separate efficacy analysis comprised 11 nonambulatory, treatment-naive SMA patients (18.1 ± 6.8 years) with three SMN2 copies and complex spine anatomy. Results: In the safety analysis, 14 treatment-related adverse events (AEs) occurred among 12 (71%) participants; all were related to the SIC and not nusinersen. Device- related AEs interfered with 2.5% of nusinersen doses. Four SICs (24%) required surgical revision due to mechanical malfunction with or without cerebrospinal fluid leak (n = 2), and one (6%) was removed due to Staphylococcus epidermidis meningitis. In the efficacy analysis, mean performance on the nine-hole peg test improved in domi- nant (15.9%, P = 0.012) and nondominant (19.0%, P = 0.008) hands and grip strength increased by 44.9% (P = 0.031). We observed no significant changes in motor scales, muscle force, pulmonary function, or SMA biomarkers. All participants in the efficacy cohort reported one or more subjective improvement(s) in endurance, purposeful hand use, arm strength, head control, and/or speech. Discussion: For SMA patients with complex spine anatomy, the SIC allows for reliable outpatient administration of nusinersen that results in meaningful improvements in upper limb function, but introduces risks of technical malfunction and iatrogenic infection.
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Title: Metabolic Control and “Ideal” Outcomes in Liver Transplantation for Maple Syrup Urine Disease Published: October 1, 2021 Publication: The Journal of Pediatrics

Authors: Caroline B Ewing, Kyle A Soltys, Kevin A Strauss, Rakesh Sindhi, Jerry Vockley, Patrick McKiernan, Robert H Squires, Geoffrey Bond, Armando Ganoza, Ajai Khanna, George V Mazariegos, James E Squires

Abstract:
To assess outcomes following liver transplantation for maple syrup urine disease by determining attainment and sustainability of metabolic control and apply an "ideal" outcome composite in long-term survivors.
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Title: Clinical Trial and Postmarketing Safety of Onasemnogene Abeparvovec Therapy Published: October 1, 2021 Publication: Drug Safety

Authors: John W. Day, Jerry R Mendell, Eugenio Mercuri, Richard S Finkel, Kevin A. Strauss, Aaron Kleyn, Sitra Tauscher-Wisniewski, Francis Fonyuy Tukov, Sandra P Reyna, Deepa H Chand

Abstract:
This is the first description of safety data for intravenous onasemnogene abeparvovec, the only approved systemically administered gene-replacement therapy for spinal muscular atrophy.
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Title: A biallelic SNIP1 Amish founder variant causes a recognizable neurodevelopmental disorder Published: September 27, 2021 Publication: PLOS Genetics

Authors: Zineb Ammous, Lettie E Rawlins, Hannah Jones, Joseph S Leslie, Olivia Wenger, Ethan Scott, Jim Deline, Tom Herr, Rebecca Evans, Angela Scheid, Joanna Kennedy, Barry A Chioza, Ryan M Ames, Harold E Cross, Erik G Puffenberger, Lorna Harries, Emma L Baple, Andrew H Crosby

Abstract:
SNIP1 (Smad nuclear interacting protein 1) is a widely expressed transcriptional suppressor of the TGF-β signal-transduction pathway which plays a key role in human spliceosome function. Here, we describe extensive genetic studies and clinical findings of a complex inherited neurodevelopmental disorder in 35 individuals associated with a SNIP1 NM_024700.4:c.1097A>G, p.(Glu366Gly) variant, present at high frequency in the Amish community. The cardinal clinical features of the condition include hypotonia, global developmental delay, intellectual disability, seizures, and a characteristic craniofacial appearance. Our gene transcript studies in affected individuals define altered gene expression profiles of a number of molecules with well-defined neurodevelopmental and neuropathological roles, potentially explaining clinical outcomes. Together these data confirm this SNIP1 gene variant as a cause of an autosomal recessive complex neurodevelopmental disorder and provide important insight into the molecular roles of SNIP1, which likely explain the cardinal clinical outcomes in affected individuals, defining potential therapeutic avenues for future research.
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Title: Cortical overgrowth in a preclinical forebrain organoid model of CNTNAP2-associated autism spectrum disorder Published: September 1, 2021 Publication: Nature Communications

Authors: Job O de Jong, Ceyda Llapashtica, Matthieu Genestine, Kevin Strauss, Frank Provenzano, Yan Sun, Huixiang Zhu, Giuseppe P Cortese, Francesco Brundu, Karlla W Brigatti, Barbara Corneo, Bianca Migliori, Raju Tomer, Steven A Kushner, Christoph Kellendonk, Jonathan A Javitch, Bin Xu, Sander Markx

Abstract:
We utilized forebrain organoids generated from induced pluripotent stem cells of patients with a syndromic form of Autism Spectrum Disorder (ASD) with a homozygous protein-truncating mutation in CNTNAP2, to study its effects on embryonic cortical development. Patients with this mutation present with clinical characteristics of brain overgrowth. Patient-derived forebrain organoids displayed an increase in volume and total cell number that is driven by increased neural progenitor proliferation. Single-cell RNA sequencing revealed PFC-excitatory neurons to be the key cell types expressing CNTNAP2. Gene ontology analysis of differentially expressed genes (DEgenes) corroborates aberrant cellular proliferation. Moreover, the DEgenes are enriched for ASD-associated genes. The cell-type-specific signature genes of the CNTNAP2-expressing neurons are associated with clinical phenotypes previously described in patients. The organoid overgrowth phenotypes were largely rescued after correction of the mutation using CRISPR-Cas9. This CNTNAP2-organoid model provides opportunity for further mechanistic inquiry and development of new therapeutic strategies for ASD.
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Title: De novo and bi-allelic variants in AP1G1 cause neurodevelopmental disorder with developmental delay, intellectual disability, and epilepsy Published: July 1, 2021 Publication: The American Journal of Human Genetics

Authors: Muhammad A Usmani, Zubair M Ahmed, Magini Pamela, Victor Murcia Pienkowski, Kristen J Rasmussen, Rebecca Hernan, Faiza Rasheed, Mureed Hussain, Mohsin Shahzad, Brendan C Lanpher, Zhiyv Niu, Foong-Yen Lim, Tommaso Pippucci, Rafal Ploski, Verena Kraus, Karolina Matuszewska, Flavia Palombo, Jessica Kianmahd, UCLA Clinical Genomics Center; Julian A Martinez-Agosto, Hane Lee, Emma Colao, M Mahdi Motazacker, Karlla W Brigatti, Erik G Puffenberger, S Amer Riazuddin, Claudia Gonzaga-Jauregui, Wendy K Chung, Matias Wagner, Matthew J Schultz, Marco Seri, Anneke J A Kievit, Nicola Perrotti, J S Klein Wassink-Ruiter, Hans van Bokhoven, Sheikh Riazuddin, Saima Riazuddin

Abstract:
Adaptor protein (AP) complexes mediate selective intracellular vesicular trafficking and polarized localization of somatodendritic proteins in neurons. Disease-causing alleles of various subunits of AP complexes have been implicated in several heritable human disorders, including intellectual disabilities (IDs). Here, we report two bi-allelic (c.737C>A [p.Pro246His] and c.1105A>G [p.Met369Val]) and eight de novo heterozygous variants (c.44G>A [p.Arg15Gln], c.103C>T [p.Arg35Trp], c.104G>A [p.Arg35Gln], c.229delC [p.Gln77Lys∗11], c.399_400del [p.Glu133Aspfs∗37], c.747G>T [p.Gln249His], c.928-2A>C [p.?], and c.2459C>G [p.Pro820Arg]) in AP1G1, encoding gamma-1 subunit of adaptor-related protein complex 1 (AP1γ1), associated with a neurodevelopmental disorder (NDD) characterized by mild to severe ID, epilepsy, and developmental delay in eleven families from different ethnicities. The AP1γ1-mediated adaptor complex is essential for the formation of clathrin-coated intracellular vesicles. In silico analysis and 3D protein modeling simulation predicted alteration of AP1γ1 protein folding for missense variants, which was consistent with the observed altered AP1γ1 levels in heterologous cells. Functional studies of the recessively inherited missense variants revealed no apparent impact on the interaction of AP1γ1 with other subunits of the AP-1 complex but rather showed to affect the endosome recycling pathway. Knocking out ap1g1 in zebrafish leads to severe morphological defect and lethality, which was significantly rescued by injection of wild-type AP1G1 mRNA and not by transcripts encoding the missense variants. Furthermore, microinjection of mRNAs with de novo missense variants in wild-type zebrafish resulted in severe developmental abnormalities and increased lethality. We conclude that de novo and bi-allelic variants in AP1G1 are associated with neurodevelopmental disorder in diverse populations.
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Title: AAV-Mediated Gene Therapy for Glycosphingolipid Biosynthesis Deficiencies Published: June 1, 2021 Publication: Trends in Molecular Medicine

Authors: Huiya Yang, Robert H Brown Jr, Dan Wang, Kevin A Strauss, Guangping Gao

Abstract:
De novo glycosphingolipid (GSL) biosynthesis defects cause severe neurological diseases, including hereditary sensory and autonomic neuropathy type 1A (HSAN1A), GM3 synthase deficiency, and hereditary spastic paraplegia type 26 (HSPG26), each lacking effective treatment. Recombinant adeno-associated virus (AAV)-mediated gene therapy has emerged as a powerful treatment for monogenic diseases and might be particularly suitable for these neurological conditions.
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