In Silico Characterization of Two Adjacent Novel Homozygous Nucleotide Variations in the PEX6 Gene Predict L898V Mutation to Enhance Infantile Refsum Disease and Heimler Syndrome
Main Article Content
Abstract
Background: Zellweger spectrum disorders are autosomal recessive in origin due to defects in peroxisome biogenesis and with variable severity. The present work aims to characterize a South Asian Indian Zellweger spectrum disorder family with PEX6 mutation for a genotype-phenotype association.
Method: The affected and unaffected individuals in the family were evaluated. A comprehensive examination of the ocular, auditory, dental, integumentary, neuronal, hepato-renal, endocrine, skeletal, cardiac, and other systems was conducted. Investigations deemed fit for diagnosis and management were done. Karyotyping and molecular genetic screening of the peripheral venous blood were performed for aneuploidy and mutation detection. Retinal fundus photograph, optical coherence tomography, bilateral audiogram, magnetic resonance imaging of the brain, ultrasonography of the abdomen, electrocardiography, and echocardiogram were performed. Any non-synonymous nucleotide variations detected were analyzed using in silico methods.
Results: The proband was born of consanguinity and had retinitis pigmentosa in both eyes, bilateral sensorineural deafness, amelogenesis imperfecta, Beau's line, and punctate leukonychia corresponding to Heimler syndrome. In addition, the proband had developmental nuclear cataracts, ichthyosis, developmental delay, cerebellar ataxia, cognitive deficit, peripheral neuropathy, and muscle movement disorder corresponding to inherited Refsum disease. The proband did not have anosmia. The brain's magnetic resonance imaging, abdomen ultrasonography, electrocardiography, and echocardiogram were normal. The karyotyping revealed euploidy status. The molecular genetic screening detected two novel adjacent homozygous non-synonymous nucleotide variations c.2691C>A (p.Ser897Arg) and c.2692C>G (p.Leu898Val) in the PEX6 gene. The pathogenic effect, structural destabilization effect, and functional impact of the variants were analyzed through in silico methods. The L898V variant was highly pathogenic compared to the non-conserved S897R variant of PEX6, leading to structural instability and loss of functionality. The molecular dynamics simulation studies also revealed the L898V variant to cause structural instability of PEX6 with higher backbone deviations and residue-wise fluctuations.
Conclusion: This study confirms the significance of L898V variant on the functionality of PEX6 that resulted in a severe disease phenotype. Genetic counseling, followed by multidisciplinary clinical evaluation was required to manage the patient with peroxisomal biogenesis disorder. A phytanic acid-restricted diet may be beneficial to control the infantile refsum disease severity.
Article Details
How to Cite
MADHAVAN, Lashudaa Madura et al.
In Silico Characterization of Two Adjacent Novel Homozygous Nucleotide Variations in the PEX6 Gene Predict L898V Mutation to Enhance Infantile Refsum Disease and Heimler Syndrome.
Medical Research Archives, [S.l.], v. 12, n. 11, nov. 2024.
ISSN 2375-1924.
Available at: <https://esmed.org/MRA/mra/article/view/5942>. Date accessed: 12 dec. 2024.
doi: https://doi.org/10.18103/mra.v12i11.5942.
Section
Research Articles
The Medical Research Archives grants authors the right to publish and reproduce the unrevised contribution in whole or in part at any time and in any form for any scholarly non-commercial purpose with the condition that all publications of the contribution include a full citation to the journal as published by the Medical Research Archives.
References
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3. Argyriou C, D'Agostino MD, Braverman N. Peroxisome biogenesis disorders. Transl Sci Rare Dis. 2016; 1:111-144. doi: 10.3233/TRD-160003
4. Ferdinandusse S, Denis S, Dacremont G, Wanders R. Studies on the metabolic fate of n-3 polyunsaturated fatty acids. J Lipid Res. 2003; 44:1992–1997.
5. Moore SA, Hurt E, Yoder E, Sprecher H, Spector AA. Docosahexaenoic acid synthesis in human skin fibroblasts involves peroxisomal retroconversion of tetracosahexaenoic acid, J Lipid Res. 1995; 36:2433–2443.
6. Wanders RJ, van Roermund CW, van Wijland MJ, Heikoop J, Schutgens RB, Schram AW, Tager JM, van den Bosch H, Poll-Thé BT, Saudubray JM. Peroxisomal very long-chain fatty acid beta-oxidation in human skin fibroblasts: activity in Zellweger syndrome and other peroxisomal disorders. Clin Chim Acta. 1987; 166:255-63. doi: 10.1016/00098981(87)90428-1
7. Singh H and Poulos A. Distinct long chain and very long chain fatty acyl CoA synthetases in rat liver peroxisomes and microsomes. Arch Biochem Biophys. 1988; 266:486–495.
8. Street JM, Johnson DW, Singh H, Poulos A. Metabolism of saturated and polyunsaturated fatty acids by normal and Zellweger syndrome skin fibroblasts. Biochem J. 1989; 15; 260:647-55. doi: 10.1042/bj2600647.
9. Uchiyama A, Aoyama T, Kamijo K, Uchida Y, Kondo N. Orii T. Molecular cloning of cDNA encoding rat very long-chain acyl-CoA synthetase. J Biol Chem. 1996; 271:30360–30365.
10. Schepers L, VanVeldhoven PP, Casteels M, Eyssen HJ, Mannaerts GP. Presence of three acyl-CoA oxidases in rat liver peroxisomes,Aninducible fatty acyl-CoA oxidase, a noninducible fatty acyl-CoA oxidase, and a noninducible trihydroxycoprostanoyl-CoA oxidase. J Biol Chem. 1990; 265:5242–5246.
11. Mize CE, Steinberg D, Avigan J and Fales HM. A pathway for oxidative degradation of phytanic acid in mammals. Biochem Biophys Res Commun. 1966; 25:359–365.
12. Eldjarn L, Heredopathia atactica polyneuritiformis (Refsum’s disease)–a defect in the omega-oxidation mechanism of fatty acids. Scand J Clin Lab Invest. 1965; 17:178–181.
13. Schrader M, Thiemann M, Fahimi HD. Peroxisomal motility and interaction with microtubules. Microsc Res Tech. 2003; 61:171-8. doi: 10.1002/jemt.10326
14. Islinger M, Voelkl A, Fahimi HD, Schrader M. The peroxisome: an update on mysteries 2.0. Histochem Cell Biol. 2018; 150:443-471. doi: 10.1007/s00418-018-1722-5
15. Kumar R, Islinger M, Worthy H, Carmichael R, Schrader M. The peroxisome: an update on mysteries 3.0. Histochem Cell Biol. 2024; 16:99-132. doi: 10.1007/s00418-023-02259-5
16. Gould SJ, Raymond GV and Valle D, The peroxisome biogenesis disorders, In: The Metabolic and Molecular Bases of Inherited Disease. McGraw Hill International Book Company, New York, NY. 2001; 3181–3217.
17. Stoll C, Dott B, Roth MP and Alembik Y. Birth prevalence rates of skeletal dysplasias, Clin Genet. 1989; 35:88–92.
18. Klouwer FC, Berendse K, Ferdinandusse S, Wanders RJ, Engelen M, Poll-The BT. Zellweger spectrum disorders: clinical overview and management approach. Orphanet J Rare Dis. 2015; 10:151. doi: 10.1186/s13023-015-0368-9
19. Goldfischer S, Moore CL, Johnson AB, Spiro AJ, Valsamis MP, Wisniewski HK. Peroxisomal and mitochondrial defects in the cerebro-hepato-renal syndrome, Science. 1973; 182:62-64. doi: 10.1126/science.182.4107.62
20. Kelley RI, Datta NS, Dobyns WB, Hajra AK, Moser AB, Noetzel MJ. Neonatal adrenoleukodystrophy: New cases, biochemical studies, and differentiation from Zellweger and related peroxisomal polydystrophy syndromes, Am J Med Genet. 1986; 23:869-901. doi: 10.1002/ajmg.1320230404
21. Vamecq J, Draye JP, Van Hoof F, Misson JP, Evrard P, Verellen G, Eyssen HJ, Van Eldere J, Schutgens RB, Wanders RJ. Multiple peroxisomal enzymatic deficiency disorders. A comparative biochemical and morphologic study of Zellweger cerebrohepatorenal syndrome and neonatal adrenoleukodystrophy. Am J Pathol; 1986; 125:524-35.
22. Lee PR, Raymond GV. Child neurology: Zellweger syndrome. Neurology. 2013; 14:80:e207-10. doi: 10.1212/WNL.0b013e3182929f8e
23. Bose M, Yergeau C, D'Souza Y, Cuthbertson DD, Lopez MJ, Smolen AK, Braverman NE. Characterization of Severity in Zellweger Spectrum Disorder by Clinical Findings: A Scoping Review, Meta-Analysis and Medical Chart Review. Cells. 2022; 11:1891. doi: 10.3390/cells11121891
24. Powers JM, Moser HW. Peroxisomal disorders: genotype, phenotype, major neuropathologic lesions, and pathogenesis. Brain Pathol. 1998; 8:101-20. doi: 10.1111/j.1750-3639
25. Corzo D, Gibson W, Johnson K, Mitchell G, LePage G, Cox GF, Casey R, Zeiss C, Tyson H, Cutting GR, Raymond GV, Smith KD, Watkins PA, Moser AB, Moser HW, Steinberg SJ. Contiguous deletion of the X-linked adrenoleukodystrophy gene (ABCD1) and DXS1357E: a novel neonatal phenotype similar to peroxisomal biogenesis disorders. Am J Hum Genet. 2002; 70:1520-31. doi: 10.1086/340849
26. Poll-The BT, Saudubray JM, Ogier H, Schutgens RB, Wanders RJ, Schrakamp G, van den Bosch H, Trijbels JM, Poulos A, Moser HW, et al. Infantile Refsum's disease: biochemical findings suggesting multiple peroxisomal dysfunction. J Inherit Metab Dis. 1986; 9:169-74. doi: 10.1007/BF01799455
27. Naidu S, Moser H. Infantile Refsum disease. Am J Neuroradiol. 1991; 12:1161-3.
28. Slanina AM, Coman AE, Anton-Păduraru DT, Popa E, Barbacariu CL, Novac O, Petroaie AD, Bacușcă AI, Manole M, Cosmescu A. PEX6 Mutation in a Child with Infantile Refsum Disease-A Case Report and Literature Review. Children (Basel) 2023; 10:530. doi: 10.3390/children10030530
29. Ratbi I, Falkenberg KD, Sommen M, Al-Sheqaih N, Guaoua S, Vandeweyer G, Urquhart JE, Chandler KE, Williams SG, Roberts NA, El Alloussi M, Black GC, Ferdinandusse S, Ramdi H, Heimler A, Fryer A, Lynch SA, Cooper N, Ong KR, Smith CE, Inglehearn CF, Mighell AJ, Elcock C, Poulter JA, Tischkowitz M, Davies SJ, Sefiani A, Mironov AA, Newman WG, Waterham HR, Van Camp G. Heimler Syndrome Is Caused by Hypomorphic Mutations in the Peroxisome-Biogenesis Genes PEX1 and PEX6. Am J Hum Genet. 2015; 97:535-45. doi: 10.1016/j.ajhg.2015.08.011
30. Smith CE, Poulter JA, Levin AV, Capasso JE, Price S, Ben-Yosef T, Sharony R, Newman WG, Shore RC, Brookes SJ, Mighell AJ, Inglehearn CF. Spectrum of PEX1 and PEX6 variants in Heimler syndrome. Eur J Hum Genet. 2016; 24:1565-1571. doi: 10.1038/ejhg.2016.62
31. Heimler A, Fox JE, Hershey JE, Crespi P: Sensorineural hearing loss, enamel hypoplasia, and nail abnormalities in sibs. Am J Med Genet. 1991; 39:192-195. doi: 10.1002/ajmg.1320390214
32. Neuhaus C, Eisenberger T, Decker C, Nagl S, Blank C, Pfister M, Kennerknecht I, Müller-Hofstede C, Charbel Issa P, Heller R, Beck B, Rüther K, Mitter D, Rohrschneider K, Steinhauer U, Korbmacher HM, Huhle D, Elsayed SM, Taha HM, Baig SM, Stöhr H, Preising M, Markus S, Moeller F, Lorenz B, Nagel-Wolfrum K, Khan AO, Bolz HJ. Next-generation sequencing reveals the mutational landscape of clinically diagnosed Usher syndrome: copy number variations, phenocopies, a predominant target for translational read-through, and PEX26 mutated in Heimler syndrome. Mol Genet Genomic Med. 2017; 5:531-552. doi: 10.1002/mgg3.312
33. Daich Varela M, Jani P, Zein WM, D'Souza P, Wolfe L, Chisholm J, Zalewski C, Adams D, Warner BM, Huryn LA, Hufnagel RB. The peroxisomal disorder spectrum and Heimler syndrome: Deep phenotyping and review of the literature. Am J Med Genet C Semin Med Genet. 2020; 184:618-630. doi: 10.1002/ajmg.c.31823
34. Braverman N, Steel G, Obie C, Moser A, Moser H and Gould S.J. Human PEX7 encodes the peroxisomal PTS2 receptor and is responsible for rhizomelic chondrodysplasia punctata. Nat Genet.1997; 15:369-376. doi: 10.1038/ng0497-369
35. Jacobsen JC, Glamuzina E, Taylor J, Swan B, Handisides S, Wilson C, Fietz M, van Dijk T, Appelhof B, Hill R, Marks R, Love DR, Robertson SP, Snell RG, Lehnert K. Whole Exome Sequencing Reveals Compound Heterozygosity for Ethnically Distinct PEX7 Mutations Responsible for Rhizomelic Chondrodysplasia Punctata, Type 1. Case Rep Genet. 2015; 2015:454526. doi: 10.1155/2015/454526
36. Fallatah W, Cui W, Di Pietro E, Carter GT, Pounder B, Dorninger F, Pifl C, Moser AB, Berger J, Braverman NE. A Pex7 Deficient Mouse Series Correlates Biochemical and Neurobehavioral Markers to Genotype Severity-Implications for the Disease Spectrum of Rhizomelic Chondrodysplasia Punctata Type 1. Front Cell Dev Biol. 2022 11;10:886316. doi: 10.3389/fcell.2022.886316
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