title: Extracellular matrix protein 1 gene (ECM1) mutations in lipoid proteinosis and genotype-phenotype correlation.
abstract: The autosomal recessive disorder lipoid proteinosis results from mutations in extracellular matrix protein 1 (ECM1), a glycoprotein expressed in several tissues (including skin) and composed of two alternatively spliced isoforms, ECM1a and ECM1b, the latter lacking exon 7 of this 10-exon gene (ECM1). To date, mutations that either affect ECM1a alone or perturb both ECM1 transcripts have been demonstrated in six cases. However, lipoid proteinosis is clinically heterogeneous with affected individuals displaying differing degrees of skin scarring and infiltration, variable signs of hoarseness and respiratory distress, and in some cases neurological abnormalities such as temporal lobe epilepsy. In this study, we sequenced ECM1 in 10 further unrelated patients with lipoid proteinosis to extend genotype-phenotype correlation and to add to the mutation database. We identified seven new homozygous nonsense or frameshift mutations: R53X (exon 3); 243delG (exon 4); 507delT (exon 6); 735delTG (exon 7); 785delA (exon 7); 892delC (exon 7) and 1190insC (exon 8), as well as two new compound heterozygous mutations: W160X/F167I (exon 6) and 542insAA/R243X (exons 6/7), none of which were found in controls. The mutation 507delT occurred in two unrelated subjects on different ECM1 haplotypes and may therefore represent a recurrent mutation in lipoid proteinosis. Taken with the previously documented mutations in ECM1, this study supports the view that exons 6 and 7 are the most common sites for ECM1 mutations in lipoid proteinosis. Clinically, it appears that mutations outside exon 7 are usually associated with a slightly more severe mucocutaneous lipoid proteinosis phenotype, but neurological features do not show any specific genotype-phenotype correlation.
authors.affiliation: Department of Cell and Molecular Pathology Immunofluorescence, St John's Institute of Dermatology, St Thomas' Hospital, London, UK.
authors.forename: Takahiro
authors.initials: T
authors.lastname: Hamada
authors.forename: Vesarat
authors.initials: V
authors.lastname: Wessagowit
authors.forename: Andrew P
authors.initials: AP
authors.lastname: South
authors.forename: Gabrielle H S
authors.initials: GH
authors.lastname: Ashton
authors.forename: Ien
authors.initials: I
authors.lastname: Chan
authors.forename: Noritaka
authors.initials: N
authors.lastname: Oyama
authors.forename: Apatorn
authors.initials: A
authors.lastname: Siriwattana
authors.forename: Prachiya
authors.initials: P
authors.lastname: Jewhasuchin
authors.forename: Somyot
authors.initials: S
authors.lastname: Charuwichitratana
authors.forename: Devinder M
authors.initials: DM
authors.lastname: Thappa
authors.forename: Balasubramanian
authors.initials: B
authors.lastname: Jeevankumar
authors.forename: Patsy
authors.initials: P
authors.lastname: Lenane
authors.forename: Bernice
authors.initials: B
authors.lastname: Krafchik
authors.forename: Kanokvalai
authors.initials: K
authors.lastname: Kulthanan
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Shimizu
authors.forename: Tamer I
authors.initials: TI
authors.lastname: Kaya
authors.forename: Mehmet E
authors.initials: ME
authors.lastname: Erdal
authors.forename: Mauro
authors.initials: M
authors.lastname: Paradisi
authors.forename: Amy S
authors.initials: AS
authors.lastname: Paller
authors.forename: Mariko
authors.initials: M
authors.lastname: Seishima
authors.forename: Takashi
authors.initials: T
authors.lastname: Hashimoto
authors.forename: John A
authors.initials: JA
authors.lastname: McGrath
mesh_terms: D000293:Adolescent; D000328:Adult; D001483:Base Sequence / Q000235:genetics; D002675:Child, Preschool; D018389:Codon, Nonsense; D005091:Exons / Q000235:genetics; D016326:Extracellular Matrix Proteins / Q000235:genetics*; D005260:Female; D016368:Frameshift Mutation; D005838:Genotype; D006239:Haplotypes; D006579:Heterozygote; D006720:Homozygote; D006801:Humans; D008065:Lipoid Proteinosis of Urbach and Wiethe / Q000235:genetics* / Q000473:pathology; D008297:Male; D008875:Middle Aged; D009154:Mutation / Q000235:genetics; D020125:Mutation, Missense; D010641:Phenotype; D011110:Polymorphism, Genetic; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D018389:Codon, Nonsense; C490607:ECM1 protein, human; D016326:Extracellular Matrix Proteins