Telomere Gene NHP2 Linked to Nerve-Driven Muscle Wasting in Rare Family Study

A rare genetic disorder best known for causing premature ageing, bone marrow failure and cancer susceptibility has now been shown to attack the nervous system in a way that leaves a distinctive fingerprint inside muscle. In a study published in Acta Neuropathologica, a team of Norwegian clinicians and researchers led by Doriana Misceo and Lisa Lirussi of Oslo University Hospital describes a family affected by dyskeratosis congenita caused by mutations in the NHP2 gene, and documents in unprecedented pathological detail how the resulting muscle wasting is driven not by a primary defect within the muscle fibres themselves, but by degeneration of the motor neurons and peripheral nerves that supply them. The work, published as a correspondence article in volume 152 of the journal, offers a molecular bridge between the telomere biology that defines dyskeratosis congenita and the neuromuscular degeneration that can dominate its clinical course.

Dyskeratosis congenita is a paradigmatic telomere biology disorder. Patients typically present with the classical triad of abnormal skin pigmentation, nail dystrophy and oral leukoplakia, but the most dangerous manifestations are systemic: progressive bone marrow failure, pulmonary fibrosis, liver disease and a markedly elevated risk of malignancy. The condition arises when telomeres, the repetitive DNA-protein caps at the ends of chromosomes, are maintained inadequately. Because telomeres shorten with every round of cell division, tissues that rely on continual stem cell replenishment are hit hardest, which explains the premature-ageing character of the disease. Genetically, dyskeratosis congenita is heterogeneous, with pathogenic variants identified in genes encoding components of the telomerase enzyme and its associated factors, including DKC1, TERT, TERC, NOP10, TINF2 and, since the landmark 2008 study by Vulliamy and colleagues in Proceedings of the National Academy of Sciences, NHP2.

NHP2 occupies a fascinating position at the intersection of two essential cellular machines. It is one of the four core proteins of H/ACA ribonucleoprotein particles, the small nucleolar complexes responsible for pseudouridylation, the isomerisation of uridine residues in ribosomal RNA and small nuclear RNAs. Remarkably, the same H/ACA architecture is also found in the telomerase RNA component, where the H/ACA domain serves as the binding platform that recruits NHP2, NOP10, GAR1 and dyskerin to the telomerase ribonucleoprotein. Structural work published in 2024 by Ghanim and colleagues in Nature Communications resolved the human telomerase H/ACA ribonucleoprotein at near-atomic resolution, showing precisely how these proteins cradle the RNA scaffold. When NHP2 is defective, both ribosome biogenesis and telomere maintenance are compromised, and recent biochemical studies, including work by Malinski and colleagues in Human Molecular Genetics in 2023, have demonstrated that pathological NHP2 variants destabilise the protein, impair H/ACA ribonucleoprotein complex formation and reduce telomerase activity.

Against this molecular backdrop, the clinical picture in the Norwegian family is striking. The affected individuals developed progressive muscular atrophy, and the central question the team set out to answer was whether the muscle degeneration reflected a myopathic process, in which the muscle fibres themselves fail, or a neurogenic process, in which the loss of innervation from motor neurons or peripheral axons causes the fibres to waste away secondarily. This distinction matters enormously for diagnosis, prognosis and any future therapeutic strategy, yet it can be difficult to establish in rare multisystem disorders where muscle involvement has not previously been characterised. Prior case reports, such as a 2025 description in Clinical Dysmorphology of a patient with novel phenotypic features of NHP2-related disease and a 2023 report in QJM of idiopathic non-cirrhotic portal hypertension in an NHP2-mutant patient, had already hinted that the clinical spectrum of NHP2 mutations extends well beyond the classical triad, but detailed neuromuscular pathology had remained largely undocumented.

The pathological evidence assembled by the Oslo team points decisively toward a neurogenic mechanism. In neurogenic atrophy, muscle biopsy reveals characteristic patterns that reflect the loss of axonal input: groups of small, angulated atrophic fibres scattered through the tissue, fibre type grouping as denervated fibres are reinnervated by surviving motor axons and adopt the histochemical profile of their new neighbours, and, in advanced disease, groups of atrophic fibres clustered together as entire motor units fail. These features stand in contrast to the rounded fibre hypertrophy, necrosis, regeneration and fibrofatty replacement that typify primary muscle disease. The authors’ neuropathological evaluation of the biopsies, combined with imaging and clinical neurophysiological assessment by specialists in rare neurological and congenital neuromuscular disorders at Oslo University Hospital, allowed them to localise the lesion to the motor neuron or its axon rather than to the muscle fibre membrane or the contractile apparatus.

That conclusion carries particular weight in light of what is known about long-term denervation. Studies of chronically denervated human muscle, notably the work of Kern and colleagues published in the Journal of Neuropathology and Experimental Neurology in 2004, have shown that prolonged loss of innervation causes degeneration not only of the contractile machinery but also of the excitation-contraction coupling apparatus, and that this degeneration can be partially reversed by functional electrical stimulation. In other words, once the nerve supply is lost, the muscle undergoes a stereotyped secondary degeneration that can masquerade as intrinsic muscle disease if the biopsy is interpreted in isolation. Recognising the neurogenic signature in NHP2-related dyskeratosis congenita therefore reframes the muscle wasting as a problem of the nervous system, opening the possibility that the same telomere-driven stem cell exhaustion that depletes the bone marrow may also be depleting the motor neuron pool or degrading the long peripheral axons that are among the most metabolically demanding cells in the body.

The molecular half of the study connects this pathology to the underlying genetics. Using whole-exome sequencing performed at the Norwegian High-Throughput Sequencing Centre, together with transcriptomic analysis, the researchers identified the NHP2 variant segregating with disease in the family and characterised its downstream consequences. Bioinformatics analyses supported the in vitro work conducted in the laboratory of Hilde Loge Nilsen at Akershus University Hospital and the University of Oslo, where the team examined how the mutant protein affects H/ACA ribonucleoprotein assembly and telomerase function. The convergence of clinical genetics, molecular cell biology and neuropathology in a single investigation is what distinguishes this report: rather than simply adding a phenotype to a gene, the authors trace a mechanistic pathway from a defective RNA-modifying and telomere-maintenance protein through to a specific pattern of tissue destruction that can be recognised under the microscope.

The broader significance of the finding lies in what it suggests about the vulnerability of the neuromuscular system to telomere failure. Motor neurons are among the longest-lived and largest cells in the human body, with axons extending up to a metre in length, and they are generally considered post-mitotic, which raises the question of how a telomere maintenance defect damages them. Several non-mutually-exclusive mechanisms are plausible. Telomere dysfunction triggers DNA damage signalling at chromosome ends, a process characterised by Takai, Smogorzewska and de Lange in Current Biology in 2003, and such damage responses can induce cell death or dysfunction even in non-dividing cells. Alternatively, the pseudouridylation defects caused by impaired H/ACA ribonucleoproteins could perturb ribosome biogenesis and translation quality in a way that selectively stresses neurons with extreme axonal maintenance demands. The disease is also increasingly discussed alongside motor neuron disorders, and the journal’s own subject indexing places this article within the categories of motor neuron disease, amyotrophic lateral sclerosis and neuromuscular disease, reflecting the nosological neighbourhood the finding occupies.

For clinicians, the practical message is that unexplained neurogenic muscle atrophy, particularly when accompanied by subtle features of premature ageing, cytopenias, pulmonary or hepatic fibrosis, or a family history suggestive of telomere disease, should prompt consideration of dyskeratosis congenita and testing of telomere biology genes including NHP2. Conversely, patients with known NHP2 mutations should be monitored for neuromuscular symptoms, since the atrophy documented in this family appears to be a genuine and characteristic manifestation of the disease rather than an incidental finding. Whole-body muscle MRI, whose diagnostic utility in non-5q spinal muscular atrophies was reviewed by Berling and colleagues in Neurology Genetics in 2026, may prove valuable in defining the distribution of involvement and distinguishing neurogenic patterns across the expanding family of telomere-related neuromuscular phenotypes.

The study, approved by the Regional Ethics Committee of Norway and conducted with informed consent from the participating family under the Declaration of Helsinki, exemplifies the kind of deep phenotyping that rare disease research increasingly demands. By combining genetic sequencing, molecular cell biology, electron microscopy, radiology and clinical neurology, the Oslo consortium has turned a single family’s illness into a general lesson about how defects in the cell’s RNA-processing and telomere-maintenance machinery can manifest as degeneration of the motor system. As the clinical spectrum of NHP2-related dyskeratosis congenita continues to expand, this pathological and molecular roadmap will help clinicians recognise the neuromuscular face of the disease earlier, and it gives researchers a concrete model in which to test whether protecting motor neurons or their axons can slow the devastating muscle wasting that telomere failure can ultimately inflict.

Subject of Research: Neurogenic muscular atrophy caused by NHP2 mutations in dyskeratosis congenita

Article Title: Neurogenic muscular atrophy in NHP2-related dyskeratosis congenita in a family: pathological and molecular insights

Article References: Misceo, D., Lirussi, L., Antal, E.-A., Sikiric, A., Ørstavik, K., Bjørnstad, P. M., Sundaram, A. Y. M., Elkamil, A. I., Esbensen, Q. Y., Bøker, T., Brorson, S. H., Hoddevik, E. H., Nilsen, H. L., Frengen, E., & Strømme, P. (2026). Neurogenic muscular atrophy in NHP2-related dyskeratosis congenita in a family: pathological and molecular insights. Acta Neuropathologica, 152(1), Article 45. https://doi.org/10.1007/s00401-026-03088-1

Image Credits: AI Generated

DOI: 10.1007/s00401-026-03088-1

Keywords: dyskeratosis congenita, NHP2, telomerase, telomere biology, neurogenic atrophy, motor neuron disease, H/ACA ribonucleoprotein, muscle pathology, whole-exome sequencing, rare disease, neuromuscular disorder, pseudouridylation