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A founder mutation in PEX12 among Egyptian patients in peroxisomal biogenesis disorder

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Abstract

At least 14 distinctive PEX genes function in the biogenesis of peroxisomes. Biallelic alterations in the peroxisomal biogenesis factor 12 (PEX12) gene lead to Zellweger syndrome spectrum (ZSS) with variable clinical expressivity ranging from early lethality to mildly affected with long-term survival. Herein, we define 20 patients derived from 14 unrelated Egyptian families, 19 of which show a homozygous PEX12 in-frame (c.1047_1049del p.(Gln349del)) deletion. This founder mutation, reported rarely outside of Egypt, was associated with a uniformly severe phenotype. Patients showed developmental delay in early life followed by motor and mental regression, progressive hypotonia, unsteadiness, and lack of speech. Seventeen patients had sparse hair or partial alopecia, a striking feature that was not noted previously in PEX12. Neonatal cholestasis was manifested in 2 siblings. Neurodiagnostics showed consistent cerebellar atrophy and variable white matter demyelination, axonal neuropathy in about half, and cardiomyopathy in 10% of patients. A single patient with a compound heterozygous PEX12 mutation exhibited milder features with late childhood onset with gait disturbance and learning disability. Thus, the PEX12 relatively common founder mutation accounts for the majority of PEX12-related disease in Egypt and delineates a uniform clinical and radiographic phenotype.

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References

  1. Wanders RJ, Waterham HR (2006a) Biochemistry of mammalian peroxisomes revisited. Annu Rev Biochem 75:295–332

    Article  CAS  Google Scholar 

  2. Berendse K, Engelen M, Ferdinandusse S, Majoie CBLM, Waterham HR, Vaz FM, Koelman JHTM, Barth PG, Wanders RJA, Poll-The BT (2016) Zellweger spectrum disorders: clinical manifestations in patients surviving into adulthood. J Inherit Metab Dis 39:93–106

    Article  CAS  Google Scholar 

  3. Klouwer FCC, Berendse K, Ferdinandusse S, Wanders RJA, Engelen M, Poll-The BT (2015) Zellweger spectrum disorders: clinical overview and management approach. Orphanet J Rare Dis 10:151

    Article  Google Scholar 

  4. Chang CC, Gould SJ (1998) Phenotype–genotype relationships in complementation group 3 of the peroxisome-biogenesis disorders. Am J Hum Genet 63:1294–1306

    Article  CAS  Google Scholar 

  5. Steinberg S, Chen L, Wei L, Moser A, Moser H, Cutting G, Braverman N (2004) The PEX Gene Screen: molecular diagnosis of peroxisome biogenesis disorders in the Zellweger syndrome spectrum. Mol Genet Metab 83:252–263

    Article  CAS  Google Scholar 

  6. Braverman NE, D’Agostino MD, Maclean GE (2013) Peroxisome biogenesis disorders: biological, clinical and pathophysiological perspectives. Dev Disabil Res Rev 17:187–196

    Article  Google Scholar 

  7. Crane DI (2014) Revisiting the neuropathogenesis of Zellweger syndrome. Neurochem Int 69:1–8

    Article  CAS  Google Scholar 

  8. Berger J, Dorninger F, Forss-Petter S, Kunze M (2016) Peroxisomes in brain development and function. Biochim Biophys Acta 1863:934–955

    Article  CAS  Google Scholar 

  9. Farr RL, Lismont C, Terlecky SR, Fransen M (2016) Peroxisome biogenesis in mammalian cells: the impact of genes and environment. Biochim Biophys Acta 1863:1049–1060

    Article  CAS  Google Scholar 

  10. Ebberink MS, Koster J, Visser G, Spronsen F, Stolte-Dijkstra I, Smit GPA, Fock JM, Kemp S, Wanders RJA, Waterham HR (2012) A novel defect of peroxisome division due to a homozygous non-sense mutation in the PEX11β gene. J Med Genet 49:307–313

    Article  CAS  Google Scholar 

  11. Waterham HR, Ebberink MS (2012) Genetics and molecular basis of human peroxisome biogenesis disorders. Biochim Biophys Acta 1822:1430–1441

    Article  CAS  Google Scholar 

  12. Yik WY, Steinberg SJ, Moser AB, Moser HW, Hacia JC (2009) Identification of novel mutations and sequence variation in the Zellweger syndrome spectrum of peroxisome biogenesis disorders. Hum Mutat 30:467–480

    Article  Google Scholar 

  13. Chang CC, Lee WH, Moser H, Valle D, Gould SJ (1997) Isolation of the human PEX12 gene, mutated in group 3 of the peroxisome biogenesis disorders. Nat Genet 15:385–388

    Article  CAS  Google Scholar 

  14. Chang CC, Warren DS, Sacksteder KA, Gould SJ (1999) PEX12 interacts with PEX5 and PEX10 and acts downstream of receptor docking in peroxisomal matrix protein import. J Cell Biol 147:761–774

    Article  CAS  Google Scholar 

  15. Ebberink MS, Mooijer PA, Gootjes J et al (2011) Genetic classification and mutational spectrum of more than 600 patients with a Zellweger syndrome spectrum disorder. Hum Mutat 32:59–69

    Article  CAS  Google Scholar 

  16. Gootjes J, Schmohl F, Waterham HR, Wanders RJ (2004a) Novel mutations in the PEX12 gene of patients with a peroxisome biogenesis disorder. Eur J Hum Genet 12:115–120

    Article  CAS  Google Scholar 

  17. Scott EM, Halees A, Itan Y et al (2016) Characterization of greater middle eastern genetic variation for enhanced disease gene discovery. Nat Genet 48:1071–1076

    Article  CAS  Google Scholar 

  18. Raas-Rothschild A, Wanders RJ, Mooijer PA et al (2002) A PEX6-defective peroxisomal biogenesis disorder with severe phenotype in an infant, versus mild phenotype resembling Usher syndrome in the affected parents. Am J Hum Genet 70:1062–1068

    Article  CAS  Google Scholar 

  19. Rosewich H, Ohlenbusch A, Gärtner J (2005) Genetic and clinical aspects of Zellweger spectrum patients with PEX1 mutations. J Med Genet 42:e58

    Article  CAS  Google Scholar 

  20. Regal L, Ebberink MS, Goemans N et al (2010) Mutations in PEX10 are a cause of autosomal recessive ataxia. Ann Neurol 68:259–263

    CAS  PubMed  Google Scholar 

  21. Mignarri A, Vinciguerra C, Giorgio A et al (2012) Zellweger spectrum disorder with mild phenotype caused by PEX2 gene mutations. JIMD Rep 6:43–46

    Article  Google Scholar 

  22. Matsui S, Funahashi M, Honda A, Shimozawa N (2013) Newly identified milder phenotype of peroxisome biogenesis disorder caused by mutated PEX3 gene. Brain Dev 35:842–848

    Article  Google Scholar 

  23. Braverman NE, Raymond GV, Rizzo WB, Moser AB, Wilkinson ME, Stone EM, Steinberg SJ, Wangler MF, Rush ET, Hacia JG, Bose M (2016) Peroxisome biogenesis disorders in the Zellweger spectrum: an overview of current diagnosis, clinical manifestations, and treatment guidelines. Mol Genet Metab 117:313–321

    Article  CAS  Google Scholar 

  24. Michelakakis HM, Zafeiriou DI, Moraitou MS, Gootjes J, Wanders RJ (2004) PEX1 deficiency presenting as Leber congenital amaurosis. Pediatr Neurol 31:146–149

    Article  Google Scholar 

  25. Majewski J, Wang Z, Lopez I, al Humaid S, Ren H, Racine J, Bazinet A, Mitchel G, Braverman N, Koenekoop RK (2011) A new ocular phenotype associated with an unexpected but known systemic disorder and mutation: novel use of genomic diagnostics and exome sequencing. J Med Genet 48:593–596

    Article  CAS  Google Scholar 

  26. Steinberg SJ, Dodt G, Raymond GV, Braverman NE, Moser AB, Moser HW (2006) Peroxisome biogenesis disorders. Biochim Biophys Acta 1763:1733–1748

    Article  CAS  Google Scholar 

  27. Ebberink MS, Csanyi B, Chong WK, Denis S, Sharp P, Mooijer PAW, Dekker CJM, Spooner C, Ngu LH, de Sousa C, Wanders RJA, Fietz MJ, Clayton PT, Waterham HR, Ferdinandusse S (2010) Identification of an unusual variant peroxisome biogenesis disorder caused by mutations in the PEX16 gene. J Med Genet 47:608–615

    Article  CAS  Google Scholar 

  28. Sevin C, Ferdinandusse S, Waterham HR, Wanders RJ, Aubourg P (2011) Autosomal recessive cerebellar ataxia caused by mutations in the PEX2 gene. Orphanet J Rare Dis 6:8. https://doi.org/10.1186/1750-1172-6-8

    Article  PubMed  PubMed Central  Google Scholar 

  29. Bove KE, Heubi JE, Balistreri WF, Setchell KD (2004) Bile acid synthetic defects and liver disease: a comprehensive review. Pediatr Dev Pathol 7:315–334

    Article  Google Scholar 

  30. Wanders RJ, Ferdinandusse S (2012) Peroxisomes, peroxisomal diseases, and the hepatotoxicity induced by peroxisomal metabolites. Curr Drug Metab 13:1401–1411

    Article  CAS  Google Scholar 

  31. Barth PG, Majoie CBLM, Gootjes J, Wanders RJA, Waterham HR, van der Knaap MS, de Klerk JBC, Smeitink J, Poll-The BT (2004) Neuroimaging of peroxisome biogenesis disorders (Zellweger spectrum) with prolonged survival. Neurology 62:439–444

    Article  CAS  Google Scholar 

  32. Poll-The BT, Gärtner J (2012) Clinical diagnosis, biochemical findings and MRI spectrum of peroxisomal disorders. Biochim Biophys Acta 1822:1421–1429

    Article  CAS  Google Scholar 

  33. Wanders RJ, van Roermund CW, Visser WF et al (2003) Peroxisomal fatty acid alpha-and betaoxidation in health and disease: new insights. Adv Exp Med Biol 544:293–302

    Article  CAS  Google Scholar 

  34. Wanders RJ, Waterham HR (2006b) Peroxisomal disorders: the single peroxisomal enzyme deficiencies. Biochim Biophys Acta 1763:1707–1720

    Article  CAS  Google Scholar 

  35. Steinberg S, Jones R, Tiffany C, Moser A (2008) Investigational methods for peroxisomal disorders. Curr Protoc Hum Genet Chapter 17:Unit 17.6

  36. Alshenaifi J, Ewida N, Anazi S, Shamseldin HE, Patel N, Maddirevula S, al-Sheddi T, Alomar R, Alobeid E, Ibrahim N, Hashem M, Abdulwahab F, Jacob M, Alhashem A, Alzaidan HI, Seidahmed MZ, Alhashemi N, Rawashdeh R, Eyaid W, al-Hassnan ZN, Rahbeeni Z, Alswaid A, Hadid A, Qari A, Mohammed DA, el Khashab HY, Alfadhel M, Abanemai M, Sunbul R, al Tala S, Alkhalifi S, Alkharfi T, Abouelhoda M, Monies D, al Tassan N, AlDubayan SH, Kurdi W, al-Owain M, Dasouki MJ, Kentab AY, Atyani S, Makhseed N, Faqeih E, Shaheen R, Alkuraya FS (2019) The many faces of peroxisomal disorders: lessons from a large Arab cohort. Clin Genet 95:310–319

    Article  CAS  Google Scholar 

  37. Okumoto K, Abe I, Fujiki Y (2000) Molecular anatomy of the peroxin Pex12p: ring finger domain is essential for Pex12p function and interacts with the peroxisome-targeting signal type 1-receptor Pex5p and a ring peroxin, Pex10p. J Biol Chem 275:25700–25710

    Article  CAS  Google Scholar 

  38. Sacksteder KA, Jones JM, South ST, Li X, Liu Y, Gould SJ (2000) PEX19 binds multiple peroxisomal membrane proteins, is predominantly cytoplasmic, and is required for peroxisome membrane synthesis. J Cell Biol 148:931–944

    Article  CAS  Google Scholar 

  39. Zeharia A, Ebberink MS, Wanders RJ et al (2007) A novel PEX12 mutation identified as the cause of a peroxisomal biogenesis disorder with mild clinical phenotype, mild biochemical abnormalities in fibroblasts and a mosaic catalase immunofluorescence pattern, even at 40 degrees C. J Hum Genet 52:599–606

    Article  CAS  Google Scholar 

  40. Steinberg SJ, Raymond GV, Braverman NE, Moser AB (2003) Peroxisome biogenesis disorders, Zellweger syndrome spectrum. In: Adam MP, Ardinger HH, Pagon RA, et al (eds). Gene Rev 2003, [Updated 2017]. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993–2020. Bookshelf URL: https://www.ncbi.nlm.nih.gov/books/NBK1448. Accessed 28 Nov 2019

  41. Gootjes J, Schmohl F, Mooijer PA et al (2004b) Identification of the molecular defect in patients with peroxisomal mosaicism using a novel method involving culturing of cells at 40 degrees C: implications for other inborn errors of metabolism. Hum Mutat 24:130–139

    Article  CAS  Google Scholar 

  42. Levesque S, Morin C, Guay SP, Villeneuve J, Marquis P, Yik WY, Jiralerspong S, Bouchard L, Steinberg S, Hacia JG, Dewar K, Braverman NE (2012) A founder mutation in the PEX6 gene is responsible for increased incidence of Zellweger syndrome in a French Canadian population. BMC Med Genet 13:72

    Article  CAS  Google Scholar 

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Correspondence to Maha S. Zaki.

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Zaki, M.S., Issa, M.Y., Thomas, M.M. et al. A founder mutation in PEX12 among Egyptian patients in peroxisomal biogenesis disorder. Neurol Sci 42, 2737–2745 (2021). https://doi.org/10.1007/s10072-020-04843-2

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