Skip to main content
PMC home page
American Journal of Human Genetics logoLink to American Journal of Human Genetics
. 1998 Nov;63(5):1294–1306. doi: 10.1086/302103

Phenotype-genotype relationships in complementation group 3 of the peroxisome-biogenesis disorders.

C C Chang 1, S J Gould 1
PMCID: PMC1377540  PMID: 9792857

Abstract

The peroxisome-biogenesis disorders (PBDs) are a set of often lethal genetic diseases characterized by mental retardation and defective peroxisomal matrix protein import. Mutations in PEX12 are known to underlie the disease in two patients from complementation group 3 of the PBDs. Here we show that all patients from this group carry mutations on both alleles of PEX12. A comparison between PEX12 genotypes and the clinical and cellular phenotypes of the corresponding PBD patients suggests a relatively straightforward relationship between genotype and phenotype in this group of the PBDs, such that the loss of PEX12 function leads to more-severe cellular and clinical phenotypes. However, one patient who presented relatively mild clinical and cellular phenotypes was a compound heterozygote for two seemingly severe mutations on each PEX12 allele. PEX12 mRNA present in the patient's cells was derived from only one allele, the one that carried a 2-bp deletion early in the PEX12 coding region, c.26,27Delta. The deduced protein product of this mRNA would contain only the first eight amino acids of the protein, and yet this mutant PEX12 cDNA displayed significant PEX12 activity in a functional complementation assay. Surprisingly, the PEX12/c.26, 27Delta cDNA directed the synthesis of a 29-kD PEX12 protein in vitro, a result that is consistent with translation initiation at a downstream AUG codon. Transfection studies confirmed the expression of similarly sized PEX12 proteins from the PEX12/c.26,27Delta allele. Thus, it appears that translation initiation at internal AUG codons may modulate disease phenotypes and should be considered whenever unexpectedly mild phenotypes result from severe mutations early in the coding region.

Full Text

The Full Text of this article is available as a PDF (1.8 MB).

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Belsham G. J., Sonenberg N. RNA-protein interactions in regulation of picornavirus RNA translation. Microbiol Rev. 1996 Sep;60(3):499–511. doi: 10.1128/mr.60.3.499-511.1996. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Braverman N., Steel G., Obie C., Moser A., Moser H., Gould S. J., Valle D. Human PEX7 encodes the peroxisomal PTS2 receptor and is responsible for rhizomelic chondrodysplasia punctata. Nat Genet. 1997 Apr;15(4):369–376. doi: 10.1038/ng0497-369. [DOI] [PubMed] [Google Scholar]
  3. Brul S., Westerveld A., Strijland A., Wanders R. J., Schram A. W., Heymans H. S., Schutgens R. B., van den Bosch H., Tager J. M. Genetic heterogeneity in the cerebrohepatorenal (Zellweger) syndrome and other inherited disorders with a generalized impairment of peroxisomal functions. A study using complementation analysis. J Clin Invest. 1988 Jun;81(6):1710–1715. doi: 10.1172/JCI113510. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Chang C. C., Lee W. H., Moser H., Valle D., Gould S. J. Isolation of the human PEX12 gene, mutated in group 3 of the peroxisome biogenesis disorders. Nat Genet. 1997 Apr;15(4):385–388. doi: 10.1038/ng0497-385. [DOI] [PubMed] [Google Scholar]
  5. Dietz H. C., Valle D., Francomano C. A., Kendzior R. J., Jr, Pyeritz R. E., Cutting G. R. The skipping of constitutive exons in vivo induced by nonsense mutations. Science. 1993 Jan 29;259(5095):680–683. doi: 10.1126/science.8430317. [DOI] [PubMed] [Google Scholar]
  6. Dodt G., Braverman N., Wong C., Moser A., Moser H. W., Watkins P., Valle D., Gould S. J. Mutations in the PTS1 receptor gene, PXR1, define complementation group 2 of the peroxisome biogenesis disorders. Nat Genet. 1995 Feb;9(2):115–125. doi: 10.1038/ng0295-115. [DOI] [PubMed] [Google Scholar]
  7. Dyer J. M., McNew J. A., Goodman J. M. The sorting sequence of the peroxisomal integral membrane protein PMP47 is contained within a short hydrophilic loop. J Cell Biol. 1996 Apr;133(2):269–280. doi: 10.1083/jcb.133.2.269. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Evan G. I., Lewis G. K., Ramsay G., Bishop J. M. Isolation of monoclonal antibodies specific for human c-myc proto-oncogene product. Mol Cell Biol. 1985 Dec;5(12):3610–3616. doi: 10.1128/mcb.5.12.3610. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Fukuda S., Shimozawa N., Suzuki Y., Zhang Z., Tomatsu S., Tsukamoto T., Hashiguchi N., Osumi T., Masuno M., Imaizumi K. Human peroxisome assembly factor-2 (PAF-2): a gene responsible for group C peroxisome biogenesis disorder in humans. Am J Hum Genet. 1996 Dec;59(6):1210–1220. [PMC free article] [PubMed] [Google Scholar]
  10. Gaspar M. L., Meo T., Bourgarel P., Guenet J. L., Tosi M. A single base deletion in the Tfm androgen receptor gene creates a short-lived messenger RNA that directs internal translation initiation. Proc Natl Acad Sci U S A. 1991 Oct 1;88(19):8606–8610. doi: 10.1073/pnas.88.19.8606. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Gould S. J., Keller G. A., Hosken N., Wilkinson J., Subramani S. A conserved tripeptide sorts proteins to peroxisomes. J Cell Biol. 1989 May;108(5):1657–1664. doi: 10.1083/jcb.108.5.1657. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Gould S. J., Krisans S., Keller G. A., Subramani S. Antibodies directed against the peroxisomal targeting signal of firefly luciferase recognize multiple mammalian peroxisomal proteins. J Cell Biol. 1990 Jan;110(1):27–34. doi: 10.1083/jcb.110.1.27. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Grant S. G., Jessee J., Bloom F. R., Hanahan D. Differential plasmid rescue from transgenic mouse DNAs into Escherichia coli methylation-restriction mutants. Proc Natl Acad Sci U S A. 1990 Jun;87(12):4645–4649. doi: 10.1073/pnas.87.12.4645. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Jansen G. A., Ofman R., Ferdinandusse S., Ijlst L., Muijsers A. O., Skjeldal O. H., Stokke O., Jakobs C., Besley G. T., Wraith J. E. Refsum disease is caused by mutations in the phytanoyl-CoA hydroxylase gene. Nat Genet. 1997 Oct;17(2):190–193. doi: 10.1038/ng1097-190. [DOI] [PubMed] [Google Scholar]
  15. Kozak M. The scanning model for translation: an update. J Cell Biol. 1989 Feb;108(2):229–241. doi: 10.1083/jcb.108.2.229. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Maquat L. E. When cells stop making sense: effects of nonsense codons on RNA metabolism in vertebrate cells. RNA. 1995 Jul;1(5):453–465. [PMC free article] [PubMed] [Google Scholar]
  17. McBratney S., Chen C. Y., Sarnow P. Internal initiation of translation. Curr Opin Cell Biol. 1993 Dec;5(6):961–965. doi: 10.1016/0955-0674(93)90077-4. [DOI] [PubMed] [Google Scholar]
  18. Michaud J., Brody L. C., Steel G., Fontaine G., Martin L. S., Valle D., Mitchell G. Strand-separating conformational polymorphism analysis: efficacy of detection of point mutations in the human ornithine delta-aminotransferase gene. Genomics. 1992 Jun;13(2):389–394. doi: 10.1016/0888-7543(92)90258-t. [DOI] [PubMed] [Google Scholar]
  19. Mihalik S. J., Morrell J. C., Kim D., Sacksteder K. A., Watkins P. A., Gould S. J. Identification of PAHX, a Refsum disease gene. Nat Genet. 1997 Oct;17(2):185–189. doi: 10.1038/ng1097-185. [DOI] [PubMed] [Google Scholar]
  20. Moser A. B., Rasmussen M., Naidu S., Watkins P. A., McGuinness M., Hajra A. K., Chen G., Raymond G., Liu A., Gordon D. Phenotype of patients with peroxisomal disorders subdivided into sixteen complementation groups. J Pediatr. 1995 Jul;127(1):13–22. doi: 10.1016/s0022-3476(95)70250-4. [DOI] [PubMed] [Google Scholar]
  21. Motley A. M., Hettema E. H., Hogenhout E. M., Brites P., ten Asbroek A. L., Wijburg F. A., Baas F., Heijmans H. S., Tabak H. F., Wanders R. J. Rhizomelic chondrodysplasia punctata is a peroxisomal protein targeting disease caused by a non-functional PTS2 receptor. Nat Genet. 1997 Apr;15(4):377–380. doi: 10.1038/ng0497-377. [DOI] [PubMed] [Google Scholar]
  22. Okumoto K., Fujiki Y. PEX12 encodes an integral membrane protein of peroxisomes. Nat Genet. 1997 Nov;17(3):265–266. doi: 10.1038/ng1197-265. [DOI] [PubMed] [Google Scholar]
  23. Okumoto K., Shimozawa N., Kawai A., Tamura S., Tsukamoto T., Osumi T., Moser H., Wanders R. J., Suzuki Y., Kondo N. PEX12, the pathogenic gene of group III Zellweger syndrome: cDNA cloning by functional complementation on a CHO cell mutant, patient analysis, and characterization of PEX12p. Mol Cell Biol. 1998 Jul;18(7):4324–4336. doi: 10.1128/mcb.18.7.4324. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Peabody D. S., Berg P. Termination-reinitiation occurs in the translation of mammalian cell mRNAs. Mol Cell Biol. 1986 Jul;6(7):2695–2703. doi: 10.1128/mcb.6.7.2695. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Peabody D. S., Subramani S., Berg P. Effect of upstream reading frames on translation efficiency in simian virus 40 recombinants. Mol Cell Biol. 1986 Jul;6(7):2704–2711. doi: 10.1128/mcb.6.7.2704. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. Poll-The B. T., Roels F., Ogier H., Scotto J., Vamecq J., Schutgens R. B., Wanders R. J., van Roermund C. W., van Wijland M. J., Schram A. W. A new peroxisomal disorder with enlarged peroxisomes and a specific deficiency of acyl-CoA oxidase (pseudo-neonatal adrenoleukodystrophy). Am J Hum Genet. 1988 Mar;42(3):422–434. [PMC free article] [PubMed] [Google Scholar]
  27. Portsteffen H., Beyer A., Becker E., Epplen C., Pawlak A., Kunau W. H., Dodt G. Human PEX1 is mutated in complementation group 1 of the peroxisome biogenesis disorders. Nat Genet. 1997 Dec;17(4):449–452. doi: 10.1038/ng1297-449. [DOI] [PubMed] [Google Scholar]
  28. Purdue P. E., Zhang J. W., Skoneczny M., Lazarow P. B. Rhizomelic chondrodysplasia punctata is caused by deficiency of human PEX7, a homologue of the yeast PTS2 receptor. Nat Genet. 1997 Apr;15(4):381–384. doi: 10.1038/ng0497-381. [DOI] [PubMed] [Google Scholar]
  29. Reuber B. E., Germain-Lee E., Collins C. S., Morrell J. C., Ameritunga R., Moser H. W., Valle D., Gould S. J. Mutations in PEX1 are the most common cause of peroxisome biogenesis disorders. Nat Genet. 1997 Dec;17(4):445–448. doi: 10.1038/ng1297-445. [DOI] [PubMed] [Google Scholar]
  30. Roscher A. A., Hoefler S., Hoefler G., Paschke E., Paltauf F., Moser A., Moser H. Genetic and phenotypic heterogeneity in disorders of peroxisome biogenesis--a complementation study involving cell lines from 19 patients. Pediatr Res. 1989 Jul;26(1):67–72. doi: 10.1203/00006450-198907000-00019. [DOI] [PubMed] [Google Scholar]
  31. Shimozawa N., Suzuki Y., Orii T., Moser A., Moser H. W., Wanders R. J. Standardization of complementation grouping of peroxisome-deficient disorders and the second Zellweger patient with peroxisomal assembly factor-1 (PAF-1) defect. Am J Hum Genet. 1993 Apr;52(4):843–844. [PMC free article] [PubMed] [Google Scholar]
  32. Shimozawa N., Tsukamoto T., Suzuki Y., Orii T., Shirayoshi Y., Mori T., Fujiki Y. A human gene responsible for Zellweger syndrome that affects peroxisome assembly. Science. 1992 Feb 28;255(5048):1132–1134. doi: 10.1126/science.1546315. [DOI] [PubMed] [Google Scholar]
  33. Slawecki M. L., Dodt G., Steinberg S., Moser A. B., Moser H. W., Gould S. J. Identification of three distinct peroxisomal protein import defects in patients with peroxisome biogenesis disorders. J Cell Sci. 1995 May;108(Pt 5):1817–1829. doi: 10.1242/jcs.108.5.1817. [DOI] [PubMed] [Google Scholar]
  34. Subramani S. Protein import into peroxisomes and biogenesis of the organelle. Annu Rev Cell Biol. 1993;9:445–478. doi: 10.1146/annurev.cb.09.110193.002305. [DOI] [PubMed] [Google Scholar]
  35. Suzuki Y., Jiang L. L., Souri M., Miyazawa S., Fukuda S., Zhang Z., Une M., Shimozawa N., Kondo N., Orii T. D-3-hydroxyacyl-CoA dehydratase/D-3-hydroxyacyl-CoA dehydrogenase bifunctional protein deficiency: a newly identified peroxisomal disorder. Am J Hum Genet. 1997 Nov;61(5):1153–1162. doi: 10.1086/301599. [DOI] [PMC free article] [PubMed] [Google Scholar]
  36. Swinkels B. W., Gould S. J., Bodnar A. G., Rachubinski R. A., Subramani S. A novel, cleavable peroxisomal targeting signal at the amino-terminus of the rat 3-ketoacyl-CoA thiolase. EMBO J. 1991 Nov;10(11):3255–3262. doi: 10.1002/j.1460-2075.1991.tb04889.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  37. Warren D. S., Morrell J. C., Moser H. W., Valle D., Gould S. J. Identification of PEX10, the gene defective in complementation group 7 of the peroxisome-biogenesis disorders. Am J Hum Genet. 1998 Aug;63(2):347–359. doi: 10.1086/301963. [DOI] [PMC free article] [PubMed] [Google Scholar]
  38. Yahraus T., Braverman N., Dodt G., Kalish J. E., Morrell J. C., Moser H. W., Valle D., Gould S. J. The peroxisome biogenesis disorder group 4 gene, PXAAA1, encodes a cytoplasmic ATPase required for stability of the PTS1 receptor. EMBO J. 1996 Jun 17;15(12):2914–2923. [PMC free article] [PubMed] [Google Scholar]
  39. de Vet E. C., van den Broek B. T., van den Bosch H. Nucleotide sequence of human alkyl-dihydroxyacetonephosphate synthase cDNA reveals the presence of a peroxisomal targeting signal 2. Biochim Biophys Acta. 1997 May 17;1346(1):25–29. doi: 10.1016/s0005-2760(97)00014-3. [DOI] [PubMed] [Google Scholar]
  40. van der Klei I. J., Veenhuis M. Yeast peroxisomes: function and biogenesis of a versatile cell organelle. Trends Microbiol. 1997 Dec;5(12):502–509. doi: 10.1016/S0966-842X(97)01156-6. [DOI] [PubMed] [Google Scholar]

Articles from American Journal of Human Genetics are provided here courtesy of American Society of Human Genetics

RESOURCES