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Piebaldism

Written1998-09Lidia Larizza, Alessandro Beghini
Medical Genetics, San Paolo School of Medicine, University of Milan Via A. di Rudini, 8, 20142 Milano, Italy
Updated2000-06Lidia Larizza, Alessandro Beghini
Medical Genetics, San Paolo School of Medicine, University of Milan Via A. di Rudini, 8, 20142 Milano, Italy

(Note : for Links provided by Atlas : click)
 

Identity

Atlas_Id 10030
Genes implicated inKIT  KITLG  SNAI2  
Note defect in melanocyte development; one of the first genetic disorders for which a pedigree was presented in 1786
Inheritance autosomal dominant; frequency is about 2.5/105 newborns

Clinics

Phenotype and clinics
  • congenital patches of white skin and white hair, principally located on the scalp, forehead, chest and abdomen and on the limbs; several patients report lifelong severe constipation; a hierarchical correlation has been elaborated between severe or mild phenotypic traits and the associated KIT mutations; in a few patients with interstitial deletions mental retardation and congenital anomalies have been also described
  • etiology : defective melanoblasts proliferation, survival and migration from the neural crest during development and defective migration of enteric-plexus ganglion cells from the neural crest to the gut
  • pathology : white spotting in human piebaldism results from the absence of melanocytes from the nonpigmented patches of skin and from hairbulbs in the white patches of hair; occasionally, individuals lack ganglion cells of the intestinal enteric neural plexus, which like melanoblasts, are derived from the neural crest
  • Neoplastic risk an increased risk of epithelioma has been reported
    Prognosis in contrast to vitiligo, piebaldism is both congenital and non-progressive

    Cytogenetics

    Inborn conditions a few patients with interstitial deletions of chromosome 4q12-q21.1 have been identified; they are charaterized by multiple congenital anomalies, short stature and mental retardation.

    Genes involved and Proteins

    Gene NameKIT (v-kit Hardy-Zuckerman 4 feline sarcoma viral oncogene homolog)
    Location 4q12
    DNA/RNA
    Description 21 exons
    Protein
    Description transmembrane SCF/MGF receptor with tyrosine kinase activity; binding of ligand (SCF) induces receptor dimerization, autophosphorylation and signal transduction via molecules containing SH2- domains
    Mutations
    Note see diagram: Loss-of-function mutations
    Germinal loss of function mutations resulting in haploinsufficiency of the receptor; different kinds of point mutations have been identified (diagram):
  • missense substitutions (Glu583Lys; Phe584Leu; Ala621Thr; His650Pro; Gly664Arg; Gly791Arg; Arg796Gly; Val812Gly; Glu861Ala) and small deletions (641del2; 892 del12) in the intracellular tyrosine kinase domain; correlate with severe piebald phenotypes, because of dominant-negative inhibition of the KIT receptor via formation of impaired receptor heterodimers between a normal and a mutant KIT monomer, and a 75% decrease of KIT- dependent signal transduction.
  • proximal frameshifts (84del1; 249del4); Trp557Term; and missense mutations (Cys136Arg; Ala178Thr; Met318Gly) associated with a mild piebald phenotype, the result of pure haploinsufficiency due to a 50% decrease of KIT-dependent signal transduction
  • distal frameshifts: 630insA; and splice junction mutations (IVS1+4G-A; IVS12+1G- A), located near the intracellular TK domain associated with variable phenotypes, as the truncated polypeptides via incorporation into nonfunctional receptor heterodimers would decrease KIT-dependent signal transduction by 50-75%, depending on their stability
  • complete deletions of the entire KIT gene ("null" mutations) result in a mild- intermediate phenotype.

  • Gene NamePDGFRA (platelet-derived growth factor receptor, alpha polypeptide)
    Location 4q12
    Note is also deleted in patients with interstitial cytogenetic deletions (contiguous gene syndrome)

    Gene NameKITLG (KIT ligand)
    Alias SCF/MGF
    Location 12q21.32
    Note no alteration of this gene has been so far identified in typical patients; at difference with the mouse system, where "steel" mice bearing SCF mutations show the "white spotting" phenotype likewise W mice bearing kit mutations; however, as mutations of KIT could not be detected in a consistent fraction of these patients, involvement of SCF is still an open question.

    Bibliography

    Novel mutations and deletions of the KIT (steel factor receptor) gene in human piebaldism.
    Ezoe K, Holmes SA, Ho L, Bennett CP, Bolognia JL, Brueton L, Burn J, Falabella R, Gatto EM, Ishii N
    American journal of human genetics. 1995 ; 56 (1) : 58-66.
    PMID 7529964
     
    Mutations in the ligand-binding domain of the kit receptor: an uncommon site in human piebaldism.
    Fleischman RA, Gallardo T, Mi X
    The Journal of investigative dermatology. 1996 ; 107 (5) : 703-706.
    PMID 8875953
     
    A 12-bp deletion (7818del12) in the c-kit protooncogene in a large Italian kindred with piebaldism.
    Riva P, Milani N, Gandolfi P, Larizza L
    Human mutation. 1995 ; 6 (4) : 343-345.
    PMID 8680409
     
    Piebaldism with deafness: molecular evidence for an expanded syndrome.
    Spritz RA, Beighton P
    American journal of medical genetics. 1998 ; 75 (1) : 101-103.
    PMID 9450866
     

    Citation

    This paper should be referenced as such :
    Larizza, L ; Beghini, A
    Piebaldism
    Atlas Genet Cytogenet Oncol Haematol. 2000;4(3):157-158.
    Free journal version : [ pdf ]   [ DOI ]
    On line version : http://AtlasGeneticsOncology.org/Tumors/piebaldID10030.html
    History of this paper:
    Larizza, L ; Beghini, A. Piebaldism. Atlas Genet Cytogenet Oncol Haematol. 1999;3(1):44-45.
    http://documents.irevues.inist.fr/bitstream/handle/2042/37494/09-1998-piebaldID10030.pdf


    External links

    OMIM172800
    OrphanetPiebaldism
    MeSHD016116  
    MedGenD016116  
    UMLSC0080024  
    ICD-10E70.3  
    HGMD120117
    REVIEW articlesautomatic search in PubMed
    Last year articlesautomatic search in PubMed


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