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Papers Published in 2025

Title: Complement Factor I Deficiency-Associated Neuroinflammatory Disease Among Old Order Amish Published: June 30, 2025 Publication: Journal of Allergy and Clinical Immunology

Authors: Whitney Reid MD, Laura Baas BS, Amy L. Stiegler PhD, Titus J. Boggon PhD, Portia A. Kreiger MD, Kathleen E. Sullivan MD, PhD, Edward M. Behrens MD, Vinay V.R. Kandula MD, Lambert P. van den Heuvel PhD, Karlla W. Brigatti MS, Vincent J. Carson MD, Neil Romberg MD

Abstract:
Complement factor I (CFI) deficiency is an ultra-rare inborn disorder of complement regulation that manifests with protean infectious, vasculitic, and neuroinflammatory symptoms. To functionally validate a previously unrecognized, disease-associated CFI variant (Y459S) and determine variant enrichment in the Old Order Amish population.
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Title: Immunopathological and microbial signatures of inflammatory bowel disease in partial RAG deficiency Published: May 2, 2025 Publication: Journal of Experimental Medicine

Authors: Riccardo Castagnoli, Francesca Pala, Poorani Subramanian, Cihan Oguz, Benjamin Schwarz, Ai Ing Lim, Andrew S. Burns, Elena Fontana, Marita Bosticardo, Cristina Corsino, Angelina Angelova, Ottavia M. Delmonte, Heather Kenney, Deanna Riley, Grace Smith Lisa Ott de Bruin, Lisa Ott de Bruin, Vasileios Oikonomou, Lucas Dos Santos Dias, Danielle Fink, Eric Bohrnsen, Cole D. Kimzey, Gian Luigi Marseglia, Guisela Alva-Lozada, Jenna R.E. Bergerson, Ana Brett, Karlla W. Brigatti, Dimana Dimitrova, Cullen M. Dutmer, Alexandra F. Freeman, Hanadys Ale, Steven M. Holland, Francesco Licciardi, Srdjan Pasic, Laura E. Poskitt, David E. Potts, Joseph F. Dasso, Svetlana O. Sharapova, Kevin A. Strauss, Brant R. Ward, Melis Yilmaz, Douglas B. Kuhns, Michail S. Lionakis, Stephen R. Daley, Heidi H. Kong, Julia A. Segre, Anna Villa, Stefania Pittaluga, Jolan E. Walter, Ivan Vujkovic-Cvijin, Yasmine Belkaid, Luigi D. Notarangelo

Abstract:
Partial RAG deficiency (pRD) can manifest with systemic and tissue-specific immune dysregulation, with inflammatory bowel disease (IBD) in 15% of the patients. We aimed at identifying the immunopathological and microbial signatures associated with IBD in patients with pRD and in a mouse model of pRD (Rag1w/w) with spontaneous development of colitis. pRD patients with IBD and Rag1w/w mice showed a systemic and colonic Th1/Th17 inflammatory signature. Restriction of fecal microbial diversity, abundance of pathogenic bacteria, and depletion of microbial species producing short-chain fatty acid were observed, which were associated with impaired induction of lamina propria peripheral Treg cells in Rag1w/w mice. The use of vedolizumab in Rag1w/w mice and of ustekinumab in a pRD patient were ineffective. Antibiotics ameliorated gut inflammation in Rag1w/w mice, but only bone marrow transplantation (BMT) rescued the immunopathological and microbial signatures. Our findings shed new light in the pathophysiology of gut inflammation in pRD and establish a curative role for BMT to resolve the disease phenotype.
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Title: A rare variant in GPR156 associated with depression in a Mennonite pedigree causes habenula hyperactivity and stress sensitivity in mice Published: April 14, 2025 Publication: Proceedings of the National Academy of Sciences

Authors: Bradley R. Miller, Claudia Gonzaga-Jauregui, Karlla W. Brigatti, Job de Jong, Robert S. Breese, Seung Yeon Ko, Erik G. Puffenberger, Cristopher Van Hout, Millie Young, Victor M. Luna, Jeffrey Staples, Michael B. First, Hilledna J. Gregoire, Andrew J. Dwork, Evangelos Pefanis, Shane McCarthy, Susannah Brydges, Jose Rojas, Bin Ye, Eli Stahl, Silvio Alessandro Di Gioia, Rene Hen, Kevin Elwood, Gorazd Rosoklija, Dadong Li, Scott Mellis, David Carey, Susan D. Croll, John D. Overton, Lynn E. Macdonald, Aris N. Economides, Alan R. Shuldiner, Nao Chuhma, Stephen Rayport, Najaf Amin, Steven A. Kushner, Nicole Alessandri-Haber, Sander Markx, Kevin A. Strauss

Abstract:
Major depressive disorder (MDD) is a leading cause of disability worldwide. Risk for MDD is heritable, and the genetic structure of founder populations enables investigation of rare susceptibility alleles with large effect. In an extended Old Order Mennonite family cohort, we identified a rare missense variant in GPR156 (c.1599G>T, p.Glu533Asp) associated with a two-fold increase in the relative risk of MDD. GPR156 is an orphan G protein–coupled receptor localized in the medial habenula, a region implicated in mood regulation. Insertion of a human sequence containing c.1599G>T into the murine Gpr156 locus induced medial habenula hyperactivity and abnormal stress-related behaviors. This work reveals a human variant that is associated with depression, implicates GPR156 as a target for mood regulation, and introduces informative murine models for investigating the pathophysiology and treatment of affective disorders.
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Title: BCKDHA-BCKDHB digenic gene therapy restores metabolic homeostasis in two mouse models and a calf with classic maple syrup urine disease Published: February 26, 2025 Publication: Science Translational Medicine

Authors: Jiaming Wang, Laura E. Poskitt, Jillian Gallagher, Erik G. Puffenberger, R. Max Wynn, Gauri Shisodia, David T. Chuang, Jonathan Beever, Donald L. Hardin, Karlla W. Brigatti, William C. Baker, Rachael Gately, Stephanie Bertrand, Ashlin Rodrigues, Hector R. Benatti, Toloo Taghian, Erin Hall, Rachel Prestigiacomo, Jialing Liang, Gong Chen, Xuntao Zhou, Lingzhi Ren, Nan Liu, Ran He, Qin Su, Jun Xie, Zhong Jiang, Alisha Gruntman, Heather Gray-Edwards, Guangping Gao, Kevin A. Strauss, Dan Wang

Abstract:
Classic maple syrup urine disease (MSUD) results from biallelic mutations in genes that encode the branched-chain α-ketoacid dehydrogenase E1α (BCKDHA), E1β (BCKDHB), or dihydrolipoamide branched-chain transacylase (DBT) subunits, which interact to form the mitochondrial BCKDH complex that decarboxylates ketoacid derivatives of leucine, isoleucine, and valine. MSUD is an inborn error of metabolism characterized by recurrent life-threatening neurologic crises and progressive brain injury that can only be managed with an exacting prescription diet or allogeneic liver transplant. To develop a gene replacement therapy for MSUD, we designed a dual-function recombinant adeno-associated virus serotype 9 (rAAV9) vector to deliver codon-optimized BCKDHA and BCKDHB (rAAV9.hA-BiP-hB) to the liver, muscle, heart, and brain. rAAV9.hA-BiP-hB restored coexpression of BCKDHA and BCKDHB as well as BCKDH holoenzyme activity in BCKDHA−/− HEK293T cells and did not perturb physiologic branched-chain amino acid homeostasis in wild-type mice at a systemic dose of 2.7 × 1014 vector genomes per kilogram. In two models of severe MSUD (Bckdha−/− and Bckdhb−/− mice) and a newborn calf homozygous for BCKDHA c.248C>T, one postnatal injection prevented perinatal death, normalized growth, restored coordinated expression of BCKDHA and BCKDHB in the skeletal muscle, liver, heart, and brain, and stabilized MSUD biomarkers in the face of high protein ingestion. In summary, we developed a one-time BCKDHA-BCKDHB systemic dual-gene replacement strategy that holds promise as a therapeutic alternative to prescription diet and liver transplant for treatment of MSUD types 1A and 1B, the two most common forms of MSUD in humans.
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