title: Mutation in KANK2, encoding a sequestering protein for steroid receptor coactivators, causes keratoderma and woolly hair.
abstract: BACKGROUND
  The combination of palmoplantar keratoderma and woolly hair is uncommon and reported as part of Naxos and Carvajal syndromes, both caused by mutations in desmosomal proteins and associated with cardiomyopathy. We describe two large consanguineous families with autosomal-recessive palmoplantar keratoderma and woolly hair, without cardiomyopathy and with no mutations in any known culprit gene. The aim of this study was to find the mutated gene in these families.
  
  
  RESULTS
  Using whole-exome sequencing, we identified a homozygous missense c.2009C>T mutation in KANK2 in the patients (p.Ala670Val). KANK2 encodes the steroid receptor coactivator (SRC)-interacting protein (SIP), an ankyrin repeat containing protein, which sequesters SRCs in the cytoplasm and controls transcription activation of steroid receptors, among others, also of the vitamin D receptor (VDR). The mutation in KANK2 is predicted to abolish the sequestering abilities of SIP. Indeed, vitamin D-induced transactivation was increased in patient's keratinocytes. Furthermore, SRC-2 and SRC-3, coactivators of VDR and important components of epidermal differentiation, are localised to the nucleus of epidermal basal cells in patients, in contrast to the cytoplasmic distribution in the heterozygous control.
  
  
  CONCLUSIONS
  These findings provide evidence that keratoderma and woolly hair can be caused by a non-desmosomal mechanism and further underline the importance of VDR for normal hair and skin phenotypes.
authors.affiliation: Department of Dermatology, Hadassah-Hebrew University Medical Center, Jerusalem, Israel The Center for Genetic Diseases of The Skin and Hair, Hadassah-Hebrew University Medical Center, Jerusalem, Israel.
authors.forename: Yuval
authors.initials: Y
authors.lastname: Ramot
authors.affiliation: Department of Dermatology, Hadassah-Hebrew University Medical Center, Jerusalem, Israel The Center for Genetic Diseases of The Skin and Hair, Hadassah-Hebrew University Medical Center, Jerusalem, Israel.
authors.forename: Vered
authors.initials: V
authors.lastname: Molho-Pessach
authors.affiliation: Department of Nephrology, Hadassah-Hebrew University Medical Center, Jerusalem, Israel.
authors.forename: Tomer
authors.initials: T
authors.lastname: Meir
authors.affiliation: Department of Dermatology, Hadassah-Hebrew University Medical Center, Jerusalem, Israel.
authors.forename: Ruslana
authors.initials: R
authors.lastname: Alper-Pinus
authors.affiliation: Department of Dermatology, Hadassah-Hebrew University Medical Center, Jerusalem, Israel.
authors.forename: Ihab
authors.initials: I
authors.lastname: Siam
authors.affiliation: Faculty of Medicine, The Palestinian Al Quds University, Abu Dis, The Palestinian Authority.
authors.forename: Spiro
authors.initials: S
authors.lastname: Tams
authors.affiliation: The Center for Genetic Diseases of The Skin and Hair, Hadassah-Hebrew University Medical Center, Jerusalem, Israel.
authors.forename: Sofia
authors.initials: S
authors.lastname: Babay
authors.affiliation: Department of Dermatology, Hadassah-Hebrew University Medical Center, Jerusalem, Israel The Center for Genetic Diseases of The Skin and Hair, Hadassah-Hebrew University Medical Center, Jerusalem, Israel.
authors.forename: Abraham
authors.initials: A
authors.lastname: Zlotogorski
mesh_terms: D017089:Ankyrin Repeat / Q000235:genetics; D051017:Apoptosis Regulatory Proteins; D001707:Biopsy, Needle; D002352:Carrier Proteins / Q000737:chemistry / Q000235:genetics*; D003198:Computer Simulation; D004252:DNA Mutational Analysis; D005260:Female; D006201:Hair Diseases / Q000151:congenital* / Q000235:genetics; D006801:Humans; D042541:Intracellular Space; D015603:Keratinocytes; D007645:Keratoderma, Palmoplantar / Q000235:genetics*; D008297:Male; D009154:Mutation; D051958:Nuclear Receptor Coactivator 2 / Q000737:chemistry; D056921:Nuclear Receptor Coactivator 3 / Q000737:chemistry; D010375:Pedigree; D011987:Receptors, Steroid; D012867:Skin / Q000166:cytology / Q000473:pathology; D025521:Tumor Suppressor Proteins / Q000737:chemistry / Q000235:genetics*
chemical_list: D051017:Apoptosis Regulatory Proteins; D002352:Carrier Proteins; C000613889:Kank2 protein, human; C498001:NCOA2 protein, human; D051958:Nuclear Receptor Coactivator 2; D011987:Receptors, Steroid; D025521:Tumor Suppressor Proteins; C538866:NCOA3 protein, human; D056921:Nuclear Receptor Coactivator 3