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Open Access 01-12-2022 | Research

Novel insights into PORCN mutations, associated phenotypes and pathophysiological aspects

Authors: Annabelle Arlt, Nicolai Kohlschmidt, Andreas Hentschel, Enrika Bartels, Claudia Groß, Ana Töpf, Pınar Edem, Nora Szabo, Albert Sickmann, Nancy Meyer, Ulrike Schara-Schmidt, Jarred Lau, Hanns Lochmüller, Rita Horvath, Yavuz Oktay, Andreas Roos, Semra Hiz

Published in: Orphanet Journal of Rare Diseases | Issue 1/2022

Abstract

Background

Goltz syndrome (GS) is a X-linked disorder defined by defects of mesodermal- and ectodermal-derived structures and caused by PORCN mutations. Features include striated skin-pigmentation, ocular and skeletal malformations and supernumerary or hypoplastic nipples. Generally, GS is associated with in utero lethality in males and most of the reported male patients show mosaicism (only three non-mosaic surviving males have been described so far). Also, precise descriptions of neurological deficits in GS are rare and less severe phenotypes might not only be caused by mosaicism but also by less pathogenic mutations suggesting the need of a molecular genetics and functional work-up of these rare variants.

Results

We report two cases: one girl suffering from typical skin and skeletal abnormalities, developmental delay, microcephaly, thin corpus callosum, periventricular gliosis and drug-resistant epilepsy caused by a PORCN nonsense-mutation (c.283C > T, p.Arg95Ter). Presence of these combined neurological features indicates that CNS-vulnerability might be a guiding symptom in the diagnosis of GS patients. The other patient is a boy with a supernumerary nipple and skeletal anomalies but also, developmental delay, microcephaly, cerebral atrophy with delayed myelination and drug-resistant epilepsy as predominant features. Skin abnormalities were not observed. Genotyping revealed a novel PORCN missense-mutation (c.847G > C, p.Asp283His) absent in the Genome Aggregation Database (gnomAD) but also identified in his asymptomatic mother. Given that non-random X-chromosome inactivation was excluded in the mother, fibroblasts of the index had been analyzed for PORCN protein-abundance and -distribution, vulnerability against additional ER-stress burden as well as for protein secretion revealing changes.

Conclusions

Our combined findings may suggest incomplete penetrance for the p.Asp283His variant and provide novel insights into the molecular etiology of GS by adding impaired ER-function and altered protein secretion to the list of pathophysiological processes resulting in the clinical manifestation of GS.

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Goltz RW, Peterson WC, Gorlin RJ, Ravits HG. Focal dermal hypoplasia. Arch Dermatol. 1962;86:708–17. https://doi.org/10.1001/archderm.1962.01590120006002.CrossRefPubMed

Wang X, Reid Sutton V, Omar Peraza-Llanes J, Yu Z, Rosetta R, Kou YC, Eble TN, Patel A, Thaller C, Fang P, et al. Mutations in X-linked PORCN, a putative regulator of Wnt signaling, cause focal dermal hypoplasia. Nat Genet. 2007;39(7):836–8. https://doi.org/10.1038/ng2057.CrossRefPubMed

Grzeschik KH, Bornholdt D, Oeffner F, Konig A, del Carmen BM, Enders H, Fritz B, Hertl M, Grasshoff U, Hofling K, et al. Deficiency of PORCN, a regulator of Wnt signaling, is associated with focal dermal hypoplasia. Nat Genet. 2007;39(7):833–5. https://doi.org/10.1038/ng2052.CrossRefPubMed

Paller AS. Wnt signaling in focal dermal hypoplasia. Nat Genet. 2007;39(7):820–1. https://doi.org/10.1038/ng0707-82.CrossRefPubMed

Clements SE, Mellerio JE, Holden ST, McCauley J, McGrath JA. PORCN gene mutations and the protean nature of focal dermal hypoplasia. Br J Dermatol. 2009;160(5):1103–9. https://doi.org/10.1111/j.1365-2133.2009.09048.x.CrossRefPubMed

Takada R, Satomi Y, Kurata T, Ueno N, Norioka S, Kondoh H, Takao T, Takada S. Monounsaturated fatty acid modification of Wnt protein: its role in Wnt secretion. Dev Cell. 2006;11(6):791–801. https://doi.org/10.1016/j.devcel.2006.10.003.CrossRefPubMed

Barrott JJ, Cash GM, Smith AP, Barrow JR, Murtaugh LC. Deletion of mouse Porcn blocks Wnt ligand secretion and reveals an ectodermal etiology of human focal dermal hypoplasia/Goltz syndrome. Proc Natl Acad Sci U S A. 2011;108(31):12752–7. https://doi.org/10.1073/pnas.1006437108.CrossRefPubMedPubMedCentral

Biechele S, Cox BJ, Rossant J. Porcupine homolog is required for canonical Wnt signaling and gastrulation in mouse embryos. Dev Biol. 2011;355(2):275–85. https://doi.org/10.1016/j.ydbio.2011.04.029.CrossRefPubMed

Liu J, Hsu PT, VanderWielen BA, Teng JM. Treatment of recalcitrant excessive granulation tissue with photodynamic therapy in an eight-year-old patient with focal dermal hypoplasia syndrome. Pediatr Dermatol. 2012;29(3):324–6. https://doi.org/10.1111/j.1525-1470.2011.01436.x.CrossRefPubMed

10.

Logan CY, Nusse R. The Wnt signaling pathway in development and disease. Annu Rev Cell Dev Biol. 2004;20:781–810. https://doi.org/10.1146/annurev.cellbio.20.010403.113126.CrossRefPubMed

11.

Reya T, Clevers H. Wnt signalling in stem cells and cancer. Nature. 2005;434(7035):843–50. https://doi.org/10.1038/nature03319.CrossRefPubMed

12.

Smigiel R, Jakubiak A, Lombardi MP, Jaworski W, Slezak R, Patkowski D, Hennekam RC. Co-occurrence of severe Goltz-Gorlin syndrome and pentalogy of Cantrell—case report and review of the literature. Am J Med Genet A. 2011;155A(5):1102–5. https://doi.org/10.1002/ajmg.a.33895.CrossRefPubMed

13.

Lombardi MP, Bulk S, Celli J, Lampe A, Gabbett MT, Ousager LB, van der Smagt JJ, Soller M, Stattin EL, Mannens MA, et al. Mutation update for the PORCN gene. Hum Mutat. 2011;32(7):723–8. https://doi.org/10.1002/humu.21505.CrossRefPubMed

14.

Bostwick B, Fang P, Patel A, Sutton VR. Phenotypic and molecular characterization of focal dermal hypoplasia in 18 individuals. Am J Med Genet C Semin Med Genet. 2016;172C(1):9–20. https://doi.org/10.1002/ajmg.c.31473.CrossRefPubMed

15.

Peters T, Perrier R, Haber RM. Focal dermal hypoplasia: report of a case with myelomeningocele, Arnold-Chiari malformation and hydrocephalus with a review of neurologic manifestations of Goltz syndrome. Pediatr Dermatol. 2014;31(2):220–4. https://doi.org/10.1111/pde.12267.CrossRefPubMed

16.

Pascual-Castroviejo I, Luengo dos Santos A, Baguero Paret G. Goltz syndrome: presentation of 2 cases. An Esp Pediatr. 1982;16(6):524–6.PubMed

17.

Almeida L, Anyane-Yeboa K, Grossman M, Rosen T. Myelomeningocele, Arnold-Chiari anomaly and hydrocephalus in focal dermal hypoplasia. Am J Med Genet. 1988;30(4):917–23. https://doi.org/10.1002/ajmg.1320300407.CrossRefPubMed

18.

Kanemura H, Hatakeyama K, Sugita K, Aihara M. Epilepsy in a patient with focal dermal hypoplasia. Pediatr Neurol. 2011;44(2):135–8. https://doi.org/10.1016/j.pediatrneurol.2010.08.003.CrossRefPubMed

19.

Hottinger A, Crottet J, Franceschetti A, Jadassohn W, Paillard R. Multiple abnormalities (atypical incontinentia pigmenti?, polydactylia, idiocy, coloboma of the choroid). Dermatologica. 1961;122:50–2.CrossRef

20.

Warburg M. Focal dermal hypoplasia. Ocular and general manifestations with a survey of the literature. Acta Ophthalmol (Copenh). 1970;48(3):525–36. https://doi.org/10.1111/j.1755-3768.1970.tb03754.x.CrossRef

21.

Baughman FA Jr, Worcester DD. Agenesis of the corpus callosum in a case of focal dermal hypoplasia. Mt Sinai J Med. 1970;37(6):702–9.PubMed

22.

Bornholdt D, Oeffner F, Konig A, Happle R, Alanay Y, Ascherman J, Benke PJ, Boente Mdel C, van der Burgt I, Chassaing N, et al. PORCN mutations in focal dermal hypoplasia: coping with lethality. Hum Mutat. 2009;30(5):E618-628. https://doi.org/10.1002/humu.20992.CrossRefPubMed

23.

Maas SM, Lombardi MP, van Essen AJ, Wakeling EL, Castle B, Temple IK, Kumar VK, Writzl K, Hennekam RC. Phenotype and genotype in 17 patients with Goltz-Gorlin syndrome. J Med Genet. 2009;46(10):716–20. https://doi.org/10.1136/jmg.2009.068403.CrossRefPubMed

24.

Vreeburg M, van Geel M, van den Heuij LG, Steijlen PM, van Steensel MA. Focal dermal hypoplasia in a male patient due to mosaicism for a novel PORCN single nucleotide deletion. J Eur Acad Dermatol Venereol. 2011;25(5):592–5. https://doi.org/10.1111/j.1468-3083.2010.03782.x.CrossRefPubMed

25.

Lasocki AL, Stark Z, Orchard D. A case of mosaic Goltz syndrome (focal dermal hypoplasia) in a male patient. Australas J Dermatol. 2011;52(1):48–51. https://doi.org/10.1111/j.1440-0960.2010.00662.x.CrossRefPubMed

26.

Yoshihashi H, Ohki H, Torii C, Ishiko A, Kosaki K. Survival of a male mosaic for PORCN mutation with mild focal dermal hypoplasia phenotype. Pediatr Dermatol. 2011;28(5):550–4.CrossRef

27.

Stevenson DA, Chirpich M, Contreras Y, Hanson H, Dent K. Goltz syndrome and PORCN mosaicism. Int J Dermatol. 2014;53(12):1481–4. https://doi.org/10.1111/ijd.12605.CrossRefPubMedPubMedCentral

28.

Young MP, Sawyer BL, Hartnett ME. Ophthalmologic findings in an 18-month-old boy with focal dermal hypoplasia. J AAPOS. 2014;18(2):205–7. https://doi.org/10.1016/j.jaapos.2013.11.015.CrossRefPubMedPubMedCentral

29.

Rao SS, Shenoy RD, Salian S, Girisha KM. Focal dermal hypoplasia with a de novo mutation p.E300* of PORCN gene in a male infant. Indian J Dermatol. 2016;61(6):700. https://doi.org/10.4103/0019-5154.193712.CrossRefPubMedPubMedCentral

30.

O’Connor E, Phan V, Cordts I, Cairns G, Hettwer S, Cox D, Lochmuller H, Roos A. MYO9A deficiency in motor neurons is associated with reduced neuromuscular agrin secretion. Hum Mol Genet. 2018;27(8):1434–46. https://doi.org/10.1093/hmg/ddy054.CrossRefPubMedPubMedCentral

31.

Asciolla JJ, Miele MM, Hendrickson RC, Resh MD. An in vitro fatty acylation assay reveals a mechanism for Wnt recognition by the acyltransferase porcupine. J Biol Chem. 2017;292(33):13507–13. https://doi.org/10.1074/jbc.C117.800136.CrossRefPubMedPubMedCentral

32.

Hentschel A, Czech A, Munchberg U, Freier E, Schara-Schmidt U, Sickmann A, Reimann J, Roos A. Protein signature of human skin fibroblasts allows the study of the molecular etiology of rare neurological diseases. Orphanet J Rare Dis. 2021;16(1):73. https://doi.org/10.1186/s13023-020-01669-1.CrossRefPubMedPubMedCentral

33.

Erlenhardt N, Yu H, Abiraman K, Yamasaki T, Wadiche JI, Tomita S, Bredt DS. Porcupine controls hippocampal AMPAR levels, composition, and synaptic transmission. Cell Rep. 2016;14(4):782–94. https://doi.org/10.1016/j.celrep.2015.12.078.CrossRefPubMedPubMedCentral

34.

Brady PD, Van Esch H, Fieremans N, Froyen G, Slavotinek A, Deprest J, Devriendt K, Vermeesch JR. Expanding the phenotypic spectrum of PORCN variants in two males with syndromic microphthalmia. Eur J Hum Genet. 2015;23(4):551–4. https://doi.org/10.1038/ejhg.2014.135.CrossRefPubMed

35.

Madan S, Liu W, Lu JT, Sutton VR, Toth B, Joe P, Waterson JR, Gibbs RA, Van den Veyver IB, Lammer EJ, et al. A non-mosaic PORCN mutation in a male with severe congenital anomalies overlapping focal dermal hypoplasia. Mol Genet Metab Rep. 2017;12:57–61. https://doi.org/10.1016/j.ymgmr.2017.06.002.CrossRefPubMedPubMedCentral

36.

Lai SL, Chien AJ, Moon RT. Wnt/Fz signaling and the cytoskeleton: potential roles in tumorigenesis. Cell Res. 2009;19(5):532–45. https://doi.org/10.1038/cr.2009.41.CrossRefPubMed

37.

May-Simera HL, Kelley MW. Cilia, Wnt signaling, and the cytoskeleton. Cilia. 2012;1(1):7. https://doi.org/10.1186/2046-2530-1-7.CrossRefPubMedPubMedCentral

38.

Wehner D, Tsarouchas TM, Michael A, Haase C, Weidinger G, Reimer MM, Becker T, Becker CG. Wnt signaling controls pro-regenerative Collagen XII in functional spinal cord regeneration in zebrafish. Nat Commun. 2017;8(1):126. https://doi.org/10.1038/s41467-017-00143-0.CrossRefPubMedPubMedCentral

39.

Moti N, Yu J, Boncompain G, Perez F, Virshup DM. Wnt traffic from endoplasmic reticulum to filopodia. PLoS ONE. 2019;14(2):e0212711. https://doi.org/10.1371/journal.pone.0212711.CrossRefPubMedPubMedCentral

40.

Hetz C. The unfolded protein response: controlling cell fate decisions under ER stress and beyond. Nat Rev Mol Cell Biol. 2012;13(2):89–102. https://doi.org/10.1038/nrm3270.CrossRefPubMed

41.

Zhang P, Zhou L, Pei C, Lin X, Yuan Z. Dysfunction of Wntless triggers the retrograde Golgi-to-ER transport of wingless and induces ER stress. Sci Rep. 2016;6:19418. https://doi.org/10.1038/srep19418.CrossRefPubMedPubMedCentral

42.

Hetz C, Saxena S. ER stress and the unfolded protein response in neurodegeneration. Nat Rev Neurol. 2017;13(8):477–91. https://doi.org/10.1038/nrneurol.2017.99.CrossRefPubMed

43.

Roos A, Kollipara L, Buchkremer S, Labisch T, Brauers E, Gatz C, Lentz C, Gerardo-Nava J, Weis J, Zahedi RP. Cellular signature of SIL1 depletion: disease pathogenesis due to alterations in protein composition beyond the ER machinery. Mol Neurobiol. 2016;53(8):5527–41. https://doi.org/10.1007/s12035-015-9456-z.CrossRefPubMed

44.

Hensel N, Claus P. The actin cytoskeleton in SMA and ALS: how does it contribute to motoneuron degeneration? Neuroscientist. 2018;24(1):54–72. https://doi.org/10.1177/1073858417705059.CrossRefPubMed

45.

Altmann KH. The cytoskeleton and its interactions with small molecules. Bioorg Med Chem. 2014;22(18):5038–9. https://doi.org/10.1016/j.bmc.2014.06.037.CrossRefPubMed

46.

Eira J, Silva CS, Sousa MM, Liz MA. The cytoskeleton as a novel therapeutic target for old neurodegenerative disorders. Prog Neurobiol. 2016;141:61–82. https://doi.org/10.1016/j.pneurobio.2016.04.007.CrossRefPubMed

47.

Morgan MB, Truitt CA, Taira J, Somach S, Pitha JV, Everett MA. Fibronectin and the extracellular matrix in the perforating disorders of the skin. Am J Dermatopathol. 1998;20(2):147–54.CrossRef

48.

Cutrona MB, Morgan NE, Simpson JC. Heritable skeletal disorders arising from defects in processing and transport of type I procollagen from the ER: perspectives on possible therapeutic approaches. Handb Exp Pharmacol. 2018;245:191–225. https://doi.org/10.1097/00000372-199804000-00008.CrossRefPubMed

49.

Topf A, Oktay Y, Balaraju S, Yilmaz E, Sonmezler E, Yis U, Laurie S, Thompson R, Roos A, MacArthur DG, et al. Severe neurodevelopmental disease caused by a homozygous TLK2 variant. Eur J Hum Genet. 2020;28(3):383–7. https://doi.org/10.1038/s41431-019-0519-x.CrossRefPubMed

50.

Reza M, Cox D, Phillips L, Johnson D, Manoharan V, Grieves M, Davis B, Roos A, Morgan J, Hanna MG, et al. MRC centre neuromuscular biobank (Newcastle and London): supporting and facilitating rare and neuromuscular disease research worldwide. Neuromuscul Disord. 2017;27(11):1054–64. https://doi.org/10.1016/j.nmd.2017.07.001.CrossRefPubMedPubMedCentral

51.

Mingirulli N, Pyle A, Hathazi D, Alston CL, Kohlschmidt N, O’Grady G, Waddell L, Evesson F, Cooper SBT, Turner C, et al. Clinical presentation and proteomic signature of patients with TANGO2 mutations. J Inherit Metab Dis. 2020;43(2):297–308. https://doi.org/10.1002/jimd.12156.CrossRefPubMed

52.

Hathazi D, Cox D, D’Amico A, Tasca G, Charlton R, Carlier RY, Baumann J, Kollipara L, Zahedi RP, Feldmann I, et al. INPP5K and SIL1 associated pathologies with overlapping clinical phenotypes converge through dysregulation of PHGDH. Brain. 2021. https://doi.org/10.1093/brain/awab133.CrossRefPubMed

53.

Burkhart JM, Schumbrutzki C, Wortelkamp S, Sickmann A, Zahedi RP. Systematic and quantitative comparison of digest efficiency and specificity reveals the impact of trypsin quality on MS-based proteomics. J Proteomics. 2012;75(4):1454–62. https://doi.org/10.1016/j.jprot.2011.11.016.CrossRefPubMed

54.

Liebermeister W, Noor E, Flamholz A, Davidi D, Bernhardt J, Milo R. Visual account of protein investment in cellular functions. Proc Natl Acad Sci U S A. 2014;111(23):8488–93. https://doi.org/10.1073/pnas.1314810111.CrossRefPubMedPubMedCentral

55.

Snel B, Lehmann G, Bork P, Huynen MA. STRING: a web-server to retrieve and display the repeatedly occurring neighbourhood of a gene. Nucleic Acids Res. 2000;28(18):3442–4. https://doi.org/10.1093/nar/28.18.3442.CrossRefPubMedPubMedCentral

Title: Novel insights into PORCN mutations, associated phenotypes and pathophysiological aspects
Authors: Annabelle Arlt
Nicolai Kohlschmidt
Andreas Hentschel
Enrika Bartels
Claudia Groß
Ana Töpf
Pınar Edem
Nora Szabo
Albert Sickmann
Nancy Meyer
Ulrike Schara-Schmidt
Jarred Lau
Hanns Lochmüller
Rita Horvath
Yavuz Oktay
Andreas Roos
Semra Hiz
Publication date: 01-12-2022
Publisher: BioMed Central
Published in: Orphanet Journal of Rare Diseases / Issue 1/2022
Electronic ISSN: 1750-1172
DOI: https://doi.org/10.1186/s13023-021-02068-w

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Novel insights into PORCN mutations, associated phenotypes and pathophysiological aspects

Abstract

Background

Results

Conclusions

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

Background

Results

Conclusions

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