New horizons in the understanding of hereditary neuropathies – screening the genome for causative genes and gene mutations
Molecular and Cellular Neurology and Neuropathology
Final Report Abstract
In the rare disease field, genomic medicine is facing two major challenges right now: 1. Despite the availability of high-throughput sequencing methods, almost 50% of axonal hereditary neuropathies remain genetically unsolved today. This is because the responsible genes still remain to be identified and/or the underlying pathomechanisms to be understood. 2. Every individual, healthy or diseased, carries millions of variants in their genome, most of which do not cause any disease phenotype. Out of all these variants, however, it is challenging to determine the one or ones that are in fact disease causing. Therefore, it is crucial to better understand gene-disease relationships, to investigate pathogenicity prioritization tools, and incorporate functional assays. In this work, I have contributed to the discovery of four (proposed) disease genes, I have helped to implement phenotype data in the use of an AI-based variant prioritization tool called MAVERICK, I have analyzed the functional consequences of several ATP1A1 mutations in a lab assay, and I have contributed to several phenotype expansion and natural history studies. Becoming part of and learning from a global collaborative research network, I had the opportunity to work with the Genesis platform, a bioinformatic tool that enables strategic data base search for genetic questions, which I used to genetically solve cases, but also to optimize filter structures for future search strategies. I found a proposedly new ALS gene in a young patient from Turkey, helped to describe a new CADM3 disease mutation in a large family from Mali, I contributed to the discovery of COQ7, including indigenous families from Brazil, and I contributed to finding underlying genetic mutations in patients with congenital insensitivity to pain and hereditary sensory and autonomic neuropathy in patients from India and Brazil. These examples underline the urgent need for shared genetic databases: Some of these diseases are so rare that they can only be understood with reference information on the genetic and phenotypic background. Becoming a part of the international ClinGen consortium, I learned to systematically evaluate genetic mutations in terms of pathogenicity, to collect and validate co-segregation studies, and to assess and interpret functional evidence on specific pathomechanisms. Beyond that, I experienced that discovering and establishing gene-disease relationships in a scientific and clinically meaningful context requires not only international, but also interdisciplinary collaboration. Being the only clinician in a genetic research lab gave me the opportunity to drastically extend my horizons. For the first time, I was conducting my own bench work, which helped me tremendously to understand disease mechanisms and critically interpret research results. Working on functional assays on the genes ATP1A1 and COQ7, I became acquainted with tissue culture work, cloning, and viability measurements. Investigating the expression of another new disease gene, I learned to apply western blots, and for interaction studies, I conducted coimmunoprecipitation studies. In order to confirm haploinsufficiency through nonsense-mediated decay, I treated patient fibroblasts with cycloheximide and compared RNA expression, sequencing the converted cDNA. I learned how to measure sorbitol levels in cells, animal and patient materials, using mass spectrometry, and I measured nerve conduction velocities in a SORD neuropathy rodent model, thereby determining the overlapping disease phenotype. In order to promote trial readiness and conduct genotypephenotype studies, I contributed to the design and conduction of a global natural history study on SORD neuropathy in patients, thereby connecting my home center in Aachen with my host center in Miami. Likewise, I helped to collect a global case series on hereditary sensory and autonomic neuropathy cases, which is to be published soon.
Publications
- "Hereditary motor neuropathies." Current Opinion in Neurology (2020)
Maike F. Dohrn, and Mario Saporta
(See online at https://doi.org/10.1097/wco.0000000000001087) - "Targeting transthyretin–mechanism-based treatment approaches and future perspectives in hereditary amyloidosis." Journal of Neurochemistry (2020)
Maike F. Dohrn, Sandra Ihne, Ute Hegenbart, Jessica Medina, Stephan Züchner, Teresa Coelho, and Katrin Hahn
(See online at https://doi.org/10.1111/jnc.15233) - "N-terminal missense variant in PLEKHG5 associated with intermediate CMT: a case report." Journal of Neuromuscular Diseases (2021): 1-5
Danique Beijer, Kiran Polavarapu, Veeramani Preethish-Kumar, Mainak Bardhan, Maike F. Dohrn, Adriana Rebelo, Stephan Züchner, and Atchayaram Nalini
(See online at https://doi.org/10.3233/jnd-210716) - "Rare mutations in ATL3, SPTLC2 and SCN9A explaining hereditary sensory neuropathy and congenital insensitivity to pain in a Brazilian cohort." Journal of the Neurological Sciences 427 (2021): 117498
Vivian Pedigone Cintra, Maike F. Dohrn, Pedro José Tomaselli, Fernanda Barbosa Figueiredo, Sandra Elisabete Marques, Sarah Teixeira Camargos, Luiz Sergio Mageste Barbosa et al.
(See online at https://doi.org/10.1016/j.jns.2021.117498) - "BiP inactivation due to loss of the deAMPylation function of FICD causes a motor neuron disease." Genetics in medicine: official journal of the American College of Medical Genetics: S1098-3600 (2022)
Adriana P. Rebelo, Ariel Ruiz, Maike F. Dohrn, Melanie Wayand, Amjad Farooq, Matt C. Danzi, Danique Beijer et al.
(See online at https://doi.org/10.1016/j.gim.2022.08.019) - "Genetic pain loss disorders." Nature reviews. Disease primers 8, no. 1 (2022): 41
Annette Lischka, Petra Lassuthova, Arman Çakar, Christopher J. Record, Jonas Van Lent, Jonathan Baets, Maike F. Dohrn et al.
(See online at https://doi.org/10.1038/s41572-022-00365-7) - "RFC1 repeat expansions: A recurrent cause of sensory and autonomic neuropathy with cough and ataxia." European Journal of Neurology (2022)
Danique Beijer & Maike F. Dohrn, Jonathan De Winter, Sarah Fazal, Andrea Cortese, Tanya Stojkovic, Gorka Fernández-Eulate et al.
(See online at https://doi.org/10.1111/ene.15310) - „De novo ATP1A1 variants in an early-onset complex neurodevelopmental syndrome.” Neurology (2022)
Maike F. Dohrn, Adriana P. Rebelo, Siddharth Srivastava, Gerarda Cappuccio, Robert Smigiel, Alka Malhotra, Donald Basel, Ingrid M. B. H. van de Laar, Rinze F. Neuteboom, Coranne Aarts-Tesselaar, Sonal Mahida, Nicola Brunetti-Pierri, Ryan J. Taft, Stephan L. Züchner
(See online at https://doi.org/10.1212/wnl.0000000000013276) - "The phenotypic spectrum of pathogenic ATP1A1 variants expands: the novel p. P600R substitution causes demyelinating Charcot–Marie–Tooth disease." Journal of Neurology (2023): 1-15
Feride Cinarli Yuksel, Paschalis Nicolaou, Kerri Spontarelli, Maike F. Dohrn, Adriana P. Rebelo, Pantelitsa Koutsou, Anthi Georghiou et al.
(See online at https://doi.org/10.1007/s00415-023-11581-w)
