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Schlipf NA, Schüle R, Klimpe S, et al. AP5Z1/SPG48 frequency in autosomal recessive and sporadic spastic paraplegia. Mol Genet Genomic Med. 2014;2(5):379-82doi: 10.1002/mgg3.87.
Schlipf, N. A., Schüle, R., Klimpe, S., Karle, K. N., Synofzik, M., Wolf, J., Riess, O., Schöls, L., & Bauer, P. (2014). AP5Z1/SPG48 frequency in autosomal recessive and sporadic spastic paraplegia. Molecular genetics & genomic medicine, 2(5), 379-82. https://doi.org/10.1002/mgg3.87
Schlipf, Nina A, et al. "AP5Z1/SPG48 frequency in autosomal recessive and sporadic spastic paraplegia." Molecular genetics & genomic medicine vol. 2,5 (2014): 379-82. doi: https://doi.org/10.1002/mgg3.87
Schlipf NA, Schüle R, Klimpe S, Karle KN, Synofzik M, Wolf J, Riess O, Schöls L, Bauer P. AP5Z1/SPG48 frequency in autosomal recessive and sporadic spastic paraplegia. Mol Genet Genomic Med. 2014 Sep;2(5):379-82. doi: 10.1002/mgg3.87. Epub 2014 May 25. PMID: 25333062; PMCID: PMC4190872.
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Mol Genet Genomic Med. 2014 Sep;2(5):379-82. doi: 10.1002/mgg3.87. Epub 2014 May 25.

AP5Z1/SPG48 frequency in autosomal recessive and sporadic spastic paraplegia.

Molecular genetics & genomic medicine

Nina A Schlipf, Rebecca Schüle, Sven Klimpe, Kathrin N Karle, Matthis Synofzik, Julia Wolf, Olaf Riess, Ludger Schöls, Peter Bauer

Affiliations

  1. Institute of Medical Genetics and Applied Genomics, University of Tübingen Tübingen, Germany ; Institute of Human Genetics, University Medical Center Freiburg Freiburg, Germany.
  2. Clinical Neurogenetics, Department of Neurology and Hertie-Institute for Clinical Brain Research, University of Tübingen Tübingen, Germany.
  3. Department of Neurology, University of Mainz Mainz, Germany.
  4. Clinical Neurogenetics, Department of Neurology and Hertie-Institute for Clinical Brain Research, University of Tübingen Tübingen, Germany ; German Center for Neurodegenerative Diseases (DZNE) Tübingen, Germany.
  5. Institute of Medical Genetics and Applied Genomics, University of Tübingen Tübingen, Germany.

PMID: 25333062 PMCID: PMC4190872 DOI: 10.1002/mgg3.87

Abstract

Hereditary spastic paraplegias (HSP) constitute a rare and highly heterogeneous group of neurodegenerative disorders, defined clinically by progressive lower limb spasticity and pyramidal weakness. Autosomal recessive HSP as well as sporadic cases present a significant diagnostic challenge. Mutations in AP5Z1, a gene playing a role in intracellular membrane trafficking, have been recently reported to be associated with spastic paraplegia type 48 (SPG48). Our objective was to determine the relative frequency and clinical relevance of AP5Z1 mutations in a large cohort of 127 HSP patients. We applied a targeted next-generation sequencing approach to analyze all coding exons of the AP5Z1 gene. With the output of high-quality reads and a mean coverage of 51-fold, we demonstrated a robust detection of variants. One 43-year-old female with sporadic complicated paraplegia showed two heterozygous nonsynonymous variants of unknown significance (VUS3; p.[R292W];[(T756I)]). Thus, AP5Z1 gene mutations are rare, at least in Europeans. Due to its low frequency, systematic genetic testing for AP5Z1 mutations is not recommended until larger studies are performed to add further evidence. Our findings demonstrate that amplicon-based deep sequencing is technically feasible and allows a compact molecular characterization of multiple HSP patients with high accuracy.

Keywords: AP5Z1; SPG48; hereditary spastic paraplegia; targeted next-generation sequencing

References

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