Research Lab

Pathogenicity mechanism and gene therapy of neurodegenerative disorder

Hereditary spastic paraplegia (HSP) are a group of neurological disorders characterized by upper motor neuron (UMN) degeneration, leading to spasticity and weakness in the lower extremities. Currently, there is no cure for this degenerative condition. Our research group, along with others, identified an autosomal dominant HSP subtype associated with the UBAP1 (ubiquitin-associated protein 1) gene. Using CRISPR/Cas9, we established in vitro human embryonic stem cells (hESCs) and in vivo mouse models harboring the recurrent variant in UBAP1. We are investigating the molecular, neuropathological, and behavioral abnormalities in these preclinical models. We are also evaluating the therapeutic approaches to specifically silence the expression of the mutant UBAP1 and rescue the HSP phenotype.

Pathogenicity mechanism and gene therapy of neurodevelopmental disorder

Neurodevelopmental disorders (NDDs) affect brain function and development, with 90% lacking approved treatments. Understanding their pathogenic mechanisms is critical for developing precision gene therapies. We previously reported an autosomal recessive NDD associated with the Mediator complex subunit 27 (MED27) gene. Mediator is essential for transcription initiation by linking enhancers to RNA polymerase II at promoters. All MED27 patients exhibited cerebellar hypoplasia or atrophy, indicating the vulnerability of the cerebellum to MED27 alterations. Using CRISPR/Cas9, we established hESCs harboring the most recurrent variant in MED27 and generated several mouse models of the gene. We are investigating the molecular, neuropathological, and behavioral abnormalities in these preclinical models and searching candidate genes as therapeutic targets.

Functional characterization of variants of uncertain significance and antiepileptic drug selection

Epilepsy is a common neurological disease and often has a monogenic etiology, particularly involving channelopathy genes encoding voltage-gated ion channels. The pathogenic mechanisms in channelopathy epilepsies can involve either gain-of-function (GoF) or loss-of-function (LoF), which require different sets of antiepileptic drugs (AEDs) for treatment. Improper AED selection may lead to ineffective therapy or even exacerbation of seizures. Therefore, accurate molecular diagnosis and understanding the pathogenicity mechanisms of variants of uncertain significance (VUS) are crucial for effective treatment. Among early-life onset epilepsy patients underwent epilepsy gene panel testing at local hospitals, we identified VUS in sodium, potassium, and calcium channel genes. Comprehensive electrophysiological recordings were performed to assess the ion channel functional changes caused by these variants. Mutant ion channels with abnormal properties were rescued using selected AEDs, and the recorded GoF or LoF defects were compared with the patients’ AED histories. This study established a robust platform for channelopathy variant curation and AED selection, enabling effective patient management. This platform holds the potential to not only examine existing approved AEDs but also explore experimental drugs targeting ion channel genes, paving the way for personalized medicine.

1. Pathogenicity of Mediator Complex Subunit 27 (MED27) in a Neurodevelopmental Disorder with Cerebellar Atrophy.
   Yiliyaer N, Li X, Guo T, Zhou H, Gong L, Yuan L, Fu Y, Qiao Y, Lui YL, Chen N, Lin P, Cheung HH, Ko H, Meng L, Chen X, Lei Y, Kwan KM, Wang H, Gu S*
   Advanced Science. 2025 Sep 29;12(48):e05535
2. The indispensable role of Mediator complex subunit 27 during neurodevelopment.
   Li X, Yiliyaer N, Guo T, Zhao H, Lei Y*, Gu S*
   Cell & Bioscience. 2025 Jun 16;15(1):83
3. Monoallelic variation in DHX9, the gene encoding the DExH-box helicase DHX9, underlies neurodevelopment disorders and Charcot-Marie-Tooth disease.
   Calame DG, Guo T, Wang C, Garrett L, Jolly A, Dawood M, Kurolap A, Henig NZ, Fatih JM, Herman I, Du H, Mitani T, Becker L, Rathkolb B, Gerlini R, Seisenberger C, Marschall S, Hunter JV, Gerard A, Heidlebaugh A, Challman T, Spillmann RC, Jhangiani SN, Coban-Akdemir Z, Lalani S, Liu L, Revah-Politi A, Iglesias A, Guzman E, Baugh E, Boddaert N, Rondeau S, Ormieres C, Barcia G, Tan QKG, Thiffault I, Pastinen T, Sheikh K, Biliciler S, Mei D, Melani F, Shashi V, Yaron Y, Steele M, Wakeling E, Østergaard E, Nazaryan-Petersen L; Undiagnosed Diseases Network; Millan F, Santiago-Sim T, Thevenon J, Bruel AL, Thauvin-Robinet C, Popp D, Platzer K, Gawlinski P, Wiszniewski W, Marafi D, Pehlivan D, Posey JE, Gibbs RA, Gailus-Durner V, Guerrini R, Fuchs H, Hrabě de Angelis M, Hölter SM, Cheung HH, Gu S*, Lupski JR.
   The American Journal of Human Genetics. 2023 Aug;110(8):1394-1413
4. Decoding hereditary spastic paraplegia pathogenicity through transcriptomic profiling.
   Ho NJ, Chen X, Lei Y*, Gu S*
   Zoological Research. 2023;44(3):650-662
5. A robust pipeline for ranking carrier frequencies of autosomal recessive and X-linked Mendelian disorders.
   Zhu W, Wang C, Mullapudi N, Cao Y, Li L, Lo IFM, Tsui SK, Chen X, Lei Y, Gu S*
   npj Genomic Medicine. 2022 Dec 19;7(1):72
6. Truncating variants in UBAP1 associated with childhood‐onset nonsyndromic hereditary spastic paraplegia.
   Gu S, Chen CA, Rosenfeld JA, Cope H, Launay N, Flanigan KM, Waldrop MA, Schrader R, Juusola J, Goker-Alpan O, Milunsky A, Schlüter A, Troncoso M, Pujol A, Tan QK, Schaaf CP, Meng L.
   Human Mutation. 2019 Nov 25;41(3):632-640
7. Mechanisms for Complex Chromosomal Insertions.
   Gu S, Szafranski P, Akdemir ZC, Yuan B, Cooper ML, Magriñá MA, Bacino CA, Lalani SR, Breman AM, Smith JL, Patel A, Song RH, Bi W, Cheung SW, Carvalho CM, Stankiewicz P, Lupski JR.
   PLOS Genetics. 2016 Nov 23;12(11):e1006446
8. Mechanisms for the Generation of Two Quadruplications Associated with Split-Hand Malformation.
   Gu S, Posey JE, Yuan B, Carvalho CM, Luk HM, Erikson K, Lo IF, Leung GK, Pickering CR, Chung BH, Lupski JR.
   Human Mutation. 2015 Dec 2;37(2):160-164
9. Alu-mediated diverse and complex pathogenic copy-number variants within human chromosome 17 at p13.3.
   Gu S, Yuan B, Campbell IM, Beck CR, Carvalho CM, Nagamani SC, Erez A, Patel A, Bacino CA, Shaw CA, Stankiewicz P, Cheung SW, Bi W, Lupski JR.
   Human Molecular Genetics. 2015 Apr 23;24(14):4061-4077
10. Nanoparticle delivery of stable miR-199a-5p agomir improves the osteogenesis of human mesenchymal stem cells via the HIF1a pathway.
    Chen X#, Gu S#, Chen BF, Shen WL, Yin Z, Xu GW, Hu JJ, Zhu T, Li G, Wan C, Ouyang HW, Lee TL, Chan WY.
    Biomaterials. 2015 Jun;53:239-250 (#Co-first authorship)