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The second point mutation in PREPL: a case report and literature review


Prolyl endopeptidase-like (PREPL) deficiency (MIM# 616224) is a rare autosomal recessive inherited congenital myasthenic syndrome characterized by neonatal hypotonia, feeding problems, mild dysmorphism, and neuromuscular symptoms, followed by hyperphagia and obesity in later childhood. Some patients also exhibit growth deficits, sexual hormone deficiency, and cognitive impairments. This syndrome is caused by biallelic mutations in PREPL. To date, only one nucleotide deletion and seven small microdeletions in PREPL have been reported. Here we report a female patient with a novel homozygous frameshift mutation in PREPL (NM_006036.4, c.342delA:p.Val115Leufs*39). Her clinical features are similar to those of previously reported cases. The mutation is the first homozygous point mutation reported in humans.

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  1. 1.

    Engel AG, Shen XM, Selcen D, Sine SM. Congenital myasthenic syndromes: pathogenesis, diagnosis, and treatment. Lancet Neurol. 2015;14:420–34.

    Article  PubMed  PubMed Central  Google Scholar 

  2. 2.

    Bartholdi D, Asadollahi R, Oneda B, Schmitt-Mechelke T, Tonella P, Baumer A, et al. Further delineation of genotype-phenotype correlation in homozygous 2p21 deletion syndromes: first description of patients without cystinuria. Am J Med Genet A. 2013;161A:1853–9.

    Article  PubMed  Google Scholar 

  3. 3.

    Jaeken J, Martens K, Francois I, Eyskens F, Lecointre C, Derua R, et al. Deletion of PREPL, a gene encoding a putative serine oligopeptidase, in patients with hypotonia-cystinuria syndrome. Am J Hum Genet. 2006;78:38–51.

    CAS  Article  PubMed  Google Scholar 

  4. 4.

    Martens K, Heulens I, Meulemans S, Zaffanello M, Tilstra D, Hes FJ, et al. Global distribution of the most prevalent deletions causing hypotonia-cystinuria syndrome. Eur J Hum Genet. 2007;15:1029–33.

    CAS  Article  PubMed  Google Scholar 

  5. 5.

    Regal L, Aydin HI, Dieltjens AM, Van Esch H, Francois I, Okur I, et al. Two novel deletions in hypotonia-cystinuria syndrome. Mol Genet Metab. 2012;107:614–6.

    CAS  Article  PubMed  Google Scholar 

  6. 6.

    Boonen K, Regal L, Jaeken J, Creemers JW. PREPL, a prolyl endopeptidase-like enzyme by name only?—lessons from patients. CNS Neurol Disord Drug Targets. 2011;10:355–60.

    CAS  Article  PubMed  Google Scholar 

  7. 7.

    Regal L, Martensson E, Maystadt I, Voermans N, Lederer D, Burlina A. et al. PREPL deficiency: delineation of the phenotype and development of a functional blood assay. Genet Med. 2018;20:109–18.

    CAS  Article  PubMed  Google Scholar 

  8. 8.

    Regal L, Shen XM, Selcen D, Verhille C, Meulemans S, Creemers JW, et al. PREPL deficiency with or without cystinuria causes a novel myasthenic syndrome. Neurology. 2014;82:1254–60.

    Article  PubMed  PubMed Central  Google Scholar 

  9. 9.

    Legati A, Reyes A, Nasca A, Invernizzi F, Lamantea E, Tiranti V, et al. New genes and pathomechanisms in mitochondrial disorders unraveled by NGS technologies. Biochim Biophys Acta. 2016;1857:1326–35.

    CAS  Article  PubMed  Google Scholar 

  10. 10.

    Latypova X, Matsumoto N, Vinceslas-Muller C, Bezieau S, Isidor B, Miyake N. Novel KCNB1 mutation associated with non-syndromic intellectual disability. J Hum Genet. 2017;62:569–73.

    CAS  Article  PubMed  Google Scholar 

  11. 11.

    Fromer M, Moran JL, Chambert K, Banks E, Bergen SE, Ruderfer DM, et al. Discovery and statistical genotyping of copy-number variation from whole-exome sequencing depth. Am J Hum Genet. 2012;91:597–607.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  12. 12.

    Nord AS, Lee M, King MC, Walsh T. Accurate and exact CNV identification from targeted high-throughput sequence data. BMC Genomics. 2011;12:184.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  13. 13.

    Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, et al. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med. 2015;17:405–24.

    Article  PubMed  PubMed Central  Google Scholar 

  14. 14.

    Eggermann T, Spengler S, Venghaus A, Denecke B, Zerres K, Baudis M, et al. 2p21 Deletions in hypotonia-cystinuria syndrome. Eur J Med Genet. 2012;55:561–3.

    Article  PubMed  Google Scholar 

  15. 15.

    Clara R, Lowenthal A. [Familial aminoaciduria with muscular hypotonia and dwarfism]. Acad R Med Belg. 1966;6:577–611.

    CAS  Google Scholar 

  16. 16.

    Wortmann SB, Koolen DA, Smeitink JA, van den Heuvel L, Rodenburg RJ. Whole exome sequencing of suspected mitochondrial patients in clinical practice. J Inherit Metab Dis. 2015;38:437–43.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

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We thank the patient’s family for their cooperation in this study. We also thank Mr. Esteban Barnafi for his help in collecting and sending samples. We thank Barry Patel, Ph.D., from Edanz Group ( for editing a draft of this manuscript.


This work was supported by grants from Research on Measures for Intractable Diseases; Comprehensive Research on Disability Health and Welfare; the Strategic Research Program for Brain Science; Initiative on Rare and Undiagnosed Diseases in Pediatrics and Initiative on Rare and Undiagnosed Diseases for Adults from the Japan Agency for Medical Research and Development; Grants-in-Aid for Scientific Research (A and B) from the Japan Society for the Promotion of Science; Creation of Innovation Centers for Advanced Interdisciplinary Research Areas Program in the Project for Developing Innovation Systems from the Japan Science and Technology Agency; grants from the Ministry of Health, Labour and Welfare; the Takeda Science Foundation; the Yokohama Foundation for Advancement of Medical Science; and the Hayashi Memorial Foundation for Female Natural Scientists.

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Correspondence to Noriko Miyake or Naomichi Matsumoto.

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The authors declare that they have no conflict of interest.

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Silva, S., Miyake, N., Tapia, C. et al. The second point mutation in PREPL: a case report and literature review. J Hum Genet 63, 677–681 (2018).

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