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SORL1 as a Putative Candidate Gene for a Novel Recessive Form of Complicated Hereditary Spastic Paraplegia: Insights from a Deep Functional Study
Ananthapadmanabha Kotambail, Yogananda Shamamandri Markandeya, R Mahima, Ramya Sukrutha, Madhura Milind Nimonkar, Suravi Sasmita Dash, Chandrajit Prasad, Ghati Kasturirangan Chetan et al.. Clinical and Translational Neuroscience, 2025-10-01
Topic: Brain proteins, microglia and lab models
Sequencing revealed a biallelic SORL1 splice donor variant (c.1211 + 1G > A). Transcriptomics confirmed nonsense-mediated decay and aberrant splicing, predicting a disrupted reading frame. Reduced SORLA protein levels and significant enlargement of endolysosomes in patient-derived fibroblasts further cemented the pathogenicity of the variant. The probability that SORL1 acts as a recessive disease-causing gene gathers support from the following data: SORL1 genomic constraint score pRec = 1, high meiotic recombination rates on the locus, phenotype of Sorl1−/− mice reminiscent of HSP with CRV, and endolysosomal enlargement in SORL1−/− glutamatergic neurons in vitro. Taken together, SORL1 is probably a new candidate for a recessive form of complicated HSP.
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APA 7th
Kotambail, A., Markandeya, Y. S., Mahima, R., Sukrutha, R., Nimonkar, M. M., Dash, S. S., et al. (2025). SORL1 as a Putative Candidate Gene for a Novel Recessive Form of Complicated Hereditary Spastic Paraplegia: Insights from a Deep Functional Study. Clinical and Translational Neuroscience. https://doi.org/10.3390/ctn9040046
Vancouver
Kotambail A, Markandeya YS, Mahima R, Sukrutha R, Nimonkar MM, Dash SS, et al. SORL1 as a Putative Candidate Gene for a Novel Recessive Form of Complicated Hereditary Spastic Paraplegia: Insights from a Deep Functional Study. Clinical and Translational Neuroscience. 2025. doi:10.3390/ctn9040046.
BibTeX
@article{kotambail2025-d09ab756,
author = {Kotambail, Ananthapadmanabha and Markandeya, Yogananda Shamamandri and Mahima, R and Sukrutha, Ramya and Nimonkar, Madhura Milind and Dash, Suravi Sasmita and Prasad, Chandrajit and Chetan, Ghati Kasturirangan and others},
title = {{SORL1 as a Putative Candidate Gene for a Novel Recessive Form of Complicated Hereditary Spastic Paraplegia: Insights from a Deep Functional Study}},
journal = {Clinical and Translational Neuroscience},
year = {2025},
doi = {10.3390/ctn9040046},
url = {https://doi.org/10.3390/ctn9040046}
}
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Key findings
- Sequencing revealed a biallelic SORL1 splice donor variant (c.1211 + 1G > A).
- Transcriptomics confirmed nonsense-mediated decay and aberrant splicing, predicting a disrupted reading frame.
- Reduced SORLA protein levels and significant enlargement of endolysosomes in patient-derived fibroblasts further cemented the pathogenicity of the variant.
- The probability that SORL1 acts as a recessive disease-causing gene gathers support from the following data: SORL1 genomic constraint score pRec = 1, high meiotic recombination rates on the locus, phenotype of Sorl1−/− mice reminiscent of HSP with CRV, and endolysosomal enlargement in SORL1−/− glutamatergic neurons in vitro.
- Taken together, SORL1 is probably a new candidate for a recessive form of complicated HSP.
Why it matters
This study found a biallelic SORL1 splice donor variant in a patient and presents evidence that SORL1 may be a recessive disease-causing gene for a form of complicated hereditary spastic paraplegia. It concerns hereditary spastic paraplegia rather than Alzheimer's disease, and does not address treating, curing or preventing Alzheimer's.
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Study details
- Evidence strengthLow
How this study scored 26/100
Published in a peer-reviewed journal. Scored zero for study design, sample size, effect reported, studied in people and randomized / blinded because the record does not state it.
| Component | Points | Why |
|---|---|---|
| Journal tier | 7 / 10 | Tier 3 — peer-reviewed journal (Clinical and Translational Neuroscience) |
| Journal's citation record | 0 / 4 | Clinical and Translational Neuroscience: journal h-index 16 (OpenAlex, 2026-10-29) |
| Study design | 0 / 12 | No study design recorded — scores zero, not guessed (not stated in the record — scored 0) |
| Strength of evidence | 1 / 5 | Rated “low” in our summary |
| Peer-review validation | 10 / 10 | Peer-reviewed. Published as an article in a named peer-reviewed journal. |
| How recent | 4 / 5 | 2025 — within 3 year(s) of the newest study here |
| Sample size | 0 / 4 | Participant count not stated — scores zero (not stated in the record — scored 0) |
| Effect reported | 0 / 3 | No effect size reported — scores zero (not stated in the record — scored 0) |
| Studied in people | 0 / 3 | Not stated whether this was studied in people — scores zero (not stated in the record — scored 0) |
| Randomized / blinded | 0 / 2 | No randomization or blinding stated — scores zero (not stated in the record — scored 0) |
| Times cited | 0 / 7 | Cited 0 times (OpenAlex, 2026-10-10) |
| Citations per year | 0 / 5 | 0.0 citations a year over 3 year(s) since 2025 |
| Impact for its field and year | 0 / 6 | Cited 0.0× the average for papers of its field and year (OpenAlex FWCI) |
| Cited by studies here | 0 / 6 | No other study in this library cites it |
| Still being cited | 0 / 4 | Cited 0 times in 2024–2026 (2026 still in progress; OpenAlex) |
| Senior author's track record | 1 / 4 | Last-listed author Gautham Arunachal: h-index 13 (OpenAlex, whole career) |
| Institution's track record | 0 / 3 | National Institute of Mental Health and Neurosciences: institution h-index 225 (OpenAlex) |
| Multicenter collaboration | 0 / 3 | OpenAlex lists 1 institution(s) in 1 country — scores zero (affiliation lists can be incomplete) |
| Indexed in PubMed | 1 / 2 | Not in PubMed, but has a DOI |
| Free to read | 2 / 2 | Free to read |
| Total | 26 / 100 | — |
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