A Missense Mutation in the MBTPS2 Gene Underlies the X-Linked Form of Olmsted Syndrome (2012)

ichthyosis follicularis with atrichia and photophobia keratosis follicularis spinulosa decalvans membrane-bound transcription factor protease, site 2 Olmsted syndrome transient receptor potential vanilloid 3 Olmsted syndrome (OS) is a very rare, severe keratinization disorder characterized by a combination of bilateral mutilating palmoplantar keratoderma and periorificial keratotic plaques (Olmsted, 1927Olmsted H.C. Keratodermia palmaris et plantaris congenitalis.Am J Dis Child. 1927; 33: 757-764Crossref Google Scholar). The other associated features reported include corneal lesions, diffuse alopecia, digital constriction, nail dystrophy, high-tone loss of hearing, infections, and squamous cell carcinomas (Mevorah et al., 2005Mevorah B. Goldberg I. Sprecher E. et al.Olmsted syndrome: mutilating palmoplantar keratoderma with periorificial keratotic plaques.J Am Acad Dermatol. 2005; 53: S266-S272Abstract Full Text Full Text PDF PubMed Scopus (42) Google Scholar). Clinical management of OS includes topical keratolytics, surgical removal of the keratotic palmoplantar masses followed by autograft, and use of systemic retinoids with variable results (Mevorah et al., 2005Mevorah B. Goldberg I. Sprecher E. et al.Olmsted syndrome: mutilating palmoplantar keratoderma with periorificial keratotic plaques.J Am Acad Dermatol. 2005; 53: S266-S272Abstract Full Text Full Text PDF PubMed Scopus (42) Google Scholar). A total of 54 cases of OS have been reported worldwide in the literature, of which only 12 cases were familial (Lin et al., 2012Lin Z. Chen Q. Lee M. et al.Exome sequencing reveals mutations in TRPV3 as a cause of Olmsted syndrome.Am J Hum Genet. 2012; 90: 558-564Abstract Full Text Full Text PDF PubMed Scopus (238) Google Scholar; Tang et al., 2012Tang L. Zhang L. Ding H. et al.Olmsted syndrome: a new case complicated with easily broken hair and treated with oral retinoid.J Dermatol. 2012; 39: 1-2Crossref Scopus (7) Google Scholar) with different modes of inheritance (Cambiaghi et al., 1995Cambiaghi S. Tadini G. Barbareschi M. et al.Olmsted syndrome in twins.Arch Dermatol. 1995; 131: 738-739Crossref PubMed Scopus (30) Google Scholar; Larregue et al., 2000Larregue M. Callot V. Kanitakis J. et al.Olmsted syndrome: report of two new cases and literature review.J Dermatol. 2000; 27: 557-568Crossref PubMed Scopus (30) Google Scholar; Lin et al., 2012Lin Z. Chen Q. Lee M. et al.Exome sequencing reveals mutations in TRPV3 as a cause of Olmsted syndrome.Am J Hum Genet. 2012; 90: 558-564Abstract Full Text Full Text PDF PubMed Scopus (238) Google Scholar). Recently, gain-of-function mutations in the transient receptor potential vanilloid 3 gene (TRPV3) were identified as a cause of autosomal dominant OS in five sporadic and one familial case (Lin et al., 2012Lin Z. Chen Q. Lee M. et al.Exome sequencing reveals mutations in TRPV3 as a cause of Olmsted syndrome.Am J Hum Genet. 2012; 90: 558-564Abstract Full Text Full Text PDF PubMed Scopus (238) Google Scholar). It is hypothesized that OS-associated TRPV3 mutations cause deregulated TRPV3 channel activity in keratinocytes (Lin et al., 2012Lin Z. Chen Q. Lee M. et al.Exome sequencing reveals mutations in TRPV3 as a cause of Olmsted syndrome.Am J Hum Genet. 2012; 90: 558-564Abstract Full Text Full Text PDF PubMed Scopus (238) Google Scholar). However, the genetic basis of X-linked forms of OS has not been elucidated. Using whole-exome sequencing (Supplementary Materials online, Materials and Methods and Supplementary Table S1 online), we investigated the genetic basis of OS in a consanguineous extended kindred, in which the disease followed a pattern of X-linked recessive inheritance (Figure 1a). The female family members (I-1 and II-2) do not exhibit any clinical features of OS. Download .pdf (.08 MB) Help with pdf files Supplementary Materials The minimum diagnostic criteria for OS were periorificial keratotic plaques and bilateral palmoplantar transgredient keratoderma (Bergonse et al., 2003Bergonse F.N. Rabello S.M. Barreto R.L. et al.Olmsted syndrome: the clinical spectrum of mutilating palmoplantar keratoderma.Pediatr Dermatol. 2003; 20: 323-326Crossref PubMed Scopus (12) Google Scholar). The probands did not have features specific to BRESEK/BRESHECK syndrome such as hearing loss, skeletal abnormalities, or dysmorphic features. The male probands were an uncle (II-1) and nephew (III-2) (Figure 1a). The patients were born to healthy consanguineous parents after uneventful and full-term pregnancies. The clinical features for these patients have been described in detail previously (Yaghoobi et al., 2007Yaghoobi R. Omidian M. Sina N. et al.Olmsted syndrome in an Iranian family: report of two new cases.Arch Iran Med. 2007; 10: 246-249PubMed Google Scholar). In brief, II-1 presented with alopecia universalis and hyperkeratotic lesions, especially around his body orifices and palmoplantar areas at the age of 6 months. Examination revealed severe periorificial plaques around the mouth and perianal regions. The massive hyperkeratosis with painful deep fissures had resulted in flexion contracture and inability to extend the joints. The lesions were yellowish-brown, pruritic, painful, and in some areas associated with malodor or infection. The nails, which were hyperkeratotic and severely dystrophic, had a fork-like appearance and were yellow in colour. Subungual hyperkeratosis was present (Figure 1b and d). The nephew of the proband (III-2) had similar patterns of disease onset and clinical features. Further clinical information can be found in the Supplementary Materials online, Clinical Information on the Probands II-1 and III-2. Exome sequencing revealed a mutation, which to our knowledge is previously unreported: c.1391T>C (p.F464S) in exon 11 of the X-chromosome gene membrane-bound transcription factor protease, site 2 (MBTPS2) (NM_015884.3) in both male probands (Figure 2a). This mutation results in the substitution of the highly conserved phenylalanine residue at codon 464 (Figure 2b) by a serine, which PolyPhen-2 (http://genetics.bwh.harvard.edu/pph2/) predicts would be probably damaging (score=0.994). This mutation is not present in online databases dbSNP (http://www.ncbi.nlm.nih.gov/projects/SNP/), 1000 Genomes (http://www.1000genomes.org/), NHLBI exome sequencing project (http://evs.gs.washington.edu/EVS/), or the MBTPS2 gene variant database (http://www.LOVD.nl/MBTPS2). Genetic screening of other family members revealed that p.F464S segregated with the disease as an X-linked recessive mutation (Figure 1a). We did not find any novel mutations or rare single nucleotide polymorphisms or indels in TRPV3, in the gap junction genes GJB2, GJB3, GJB4, GJB6, or in DSP (desmoplakin) or JUP (plakoglobin). MBTPS2 is a zinc metalloprotease that, along with MBTPS1, mediates cleavage of signaling proteins involved in transcriptional responses of cells to sterols, including SREBPs (Sakai et al., 1998Sakai J. Nohturfft A. Goldstein J.L. et al.Cleavage of sterol regulatory element-binding proteins (SREBPs) at site-1 requires interaction with SREBP cleavage-activating protein. Evidence from in vivo competition studies.J Biol Chem. 1998; 273: 5785-5793Crossref PubMed Scopus (191) Google Scholar), and of components of the unfolded protein response such as ATF6 (Ye et al., 2000Ye J. Rawson R.B. Komuro R. et al.ER stress induces cleavage of membrane-bound ATF6 by the same proteases that process SREBPs.Mol Cell. 2000; 6: 1355-1364Abstract Full Text Full Text PDF PubMed Scopus (1355) Google Scholar). MBTPS2 mutations have been linked to three skin diseases: ichthyosis follicularis with atrichia and photophobia (IFAP) syndrome (Oeffner et al., 2009Oeffner F. Fischer G. Happle R. et al.IFAP syndrome is caused by deficiency in MBTPS2, an intramembrane zinc metalloprotease essential for cholesterol homeostasis and ER stress response.Am J Hum Genet. 2009; 84: 459-467Abstract Full Text Full Text PDF PubMed Scopus (105) Google Scholar; Ding et al., 2010Ding Y.G. Wang J.Y. Qiao J.J. et al.A novel mutation in MBTPS2 causes ichthyosis follicularis, alopecia and photophobia (IFAP) syndrome in a Chinese family.Br J Dermatol. 2010; 163: 886-889Crossref PubMed Scopus (17) Google Scholar; Tang et al., 2011Tang L. Liang J. Wang W. et al.A novel mutation in MBTPS2 causes a broad phenotypic spectrum of ichthyosis follicularis, atrichia, and photophobia syndrome in a large Chinese family.J Am Acad Dermatol. 2011; 64: 716-722Abstract Full Text Full Text PDF PubMed Scopus (17) Google Scholar), keratosis follicularis spinulosa decalvans (KFSD) (Aten et al., 2010Aten E. Brasz L.C. Bornholdt D. et al.Keratosis follicularis spinulosa decalvans is caused by mutations in MBTPS2.Hum Mut. 2010; 31: 1125-1133Crossref PubMed Scopus (56) Google Scholar), and BRESEK/BRESHECK syndrome (Naiki et al., 2012Naiki M. Mizuno S. Yamada K. et al.MBTPS2 mutation causes BRESEK/BRESHECK syndrome.Am J Med Genet A. 2012; 158A: 97-102Crossref PubMed Scopus (31) Google Scholar), suggesting the specific position of a disease-associated mutation in MBTPS2 affects the clinical presentation. In line with the X-linked inheritance, only male patients presented with full clinical disease features, whereas female carriers of MBTPS2 mutations were either phenotypically normal or showed rather mild and asymmetric symptoms. MBTPS2 has a HEIGH motif and an LDG (amino acids 466–468) motif, which are predicted to coordinate the zinc atom in the active site of the enzyme (Zelenski et al., 1999Zelenski N.G. Rawson R.B. Brown M.S. et al.Membrane topology of S2P, a protein required for intramembranous cleavage of sterol regulatory element-binding proteins.J Biol Chem. 1999; 274: 21973-21980Crossref PubMed Scopus (96) Google Scholar). In vitro functional investigations with MBTPS2 skin disease mutants revealed decreased sterol responsiveness and were predicted to deplete protease activity (Oeffner et al., 2009Oeffner F. Fischer G. Happle R. et al.IFAP syndrome is caused by deficiency in MBTPS2, an intramembrane zinc metalloprotease essential for cholesterol homeostasis and ER stress response.Am J Hum Genet. 2009; 84: 459-467Abstract Full Text Full Text PDF PubMed Scopus (105) Google Scholar; Aten et al., 2010Aten E. Brasz L.C. Bornholdt D. et al.Keratosis follicularis spinulosa decalvans is caused by mutations in MBTPS2.Hum Mut. 2010; 31: 1125-1133Crossref PubMed Scopus (56) Google Scholar), with the mutants p.R429H and p.F475S having the most profound effect (Oeffner et al., 2009Oeffner F. Fischer G. Happle R. et al.IFAP syndrome is caused by deficiency in MBTPS2, an intramembrane zinc metalloprotease essential for cholesterol homeostasis and ER stress response.Am J Hum Genet. 2009; 84: 459-467Abstract Full Text Full Text PDF PubMed Scopus (105) Google Scholar). p.R429H and p.F475S are also associated with the most severe disease phenotypes, and it is hypothesized that this is because of their close proximity to the LDG motif (Oeffner et al., 2009Oeffner F. Fischer G. Happle R. et al.IFAP syndrome is caused by deficiency in MBTPS2, an intramembrane zinc metalloprotease essential for cholesterol homeostasis and ER stress response.Am J Hum Genet. 2009; 84: 459-467Abstract Full Text Full Text PDF PubMed Scopus (105) Google Scholar; Naiki et al., 2012Naiki M. Mizuno S. Yamada K. et al.MBTPS2 mutation causes BRESEK/BRESHECK syndrome.Am J Med Genet A. 2012; 158A: 97-102Crossref PubMed Scopus (31) Google Scholar). p.F464S discovered in this study is only two codons from the LDG motif, and thus is likely to have a significantly detrimental effect on MBTPS2 function and would reflect the severity of symptoms in the OS patients. Immunohistochemical staining indicated that MBTPS2 is mainly expressed in the upper granular layer in normal skin, as previously shown (Aten et al., 2010Aten E. Brasz L.C. Bornholdt D. et al.Keratosis follicularis spinulosa decalvans is caused by mutations in MBTPS2.Hum Mut. 2010; 31: 1125-1133Crossref PubMed Scopus (56) Google Scholar); however, in OS skin, MBTPS2 was expressed throughout the epidermis (Figure 2c). There was no apparent difference in MBTPS2 localization in the skin of a KFSD patient with the p.N508S mutation (Aten et al., 2010Aten E. Brasz L.C. Bornholdt D. et al.Keratosis follicularis spinulosa decalvans is caused by mutations in MBTPS2.Hum Mut. 2010; 31: 1125-1133Crossref PubMed Scopus (56) Google Scholar). It is unclear why this is but it may be because of differences in processing of the mutants in the two diseases. In summary, we demonstrate a novel association between an MBTPS2 mutation and an X-linked form of OS. This expands the number of disorders linked to MBTPS2 mutations and reveals clinical heterogeneity associated with different MBTPS2 mutations. Written, informed consent was obtained from all family members or their legal guardians. This study was approved by the South East NHS Research Ethics Committee and was performed according to the Declaration of Helsinki Principles. We thank Barts and The London Charity for its financial support (to DPK). Supplementary material is linked to the online version of the paper at http://www.nature.com/jid