TY - JOUR
T1 - Extracellular matrix protein 1 gene (ECM1) mutations in lipoid proteinosis and genotype-phenotype correlation
AU - Hamada, Takahiro
AU - Wessagowit, Vesarat
AU - South, Andrew P.
AU - Ashton, Gabrielle H.S.
AU - Chan, Ien
AU - Oyama, Noritaka
AU - Siriwattana, Apatorn
AU - Jewhasuchin, Prachiya
AU - Charuwichitratana, Somyot
AU - Thappa, Devinder M.
AU - Lenane, Patsy
AU - Krafchik, Bernice
AU - Kulthanan, Kanokvalai
AU - Shimizu, Hiroshi
AU - Kaya, Tamer I.
AU - Erdal, Mehmet E.
AU - Paradisi, Mauro
AU - Paller, Amy S.
AU - Seishima, Mariko
AU - Hashimoto, Takashi
AU - McGrath, John A.
N1 - Funding Information:
This work was supported by the British Skin Foundation and also by the Dystrophic Epidermolysis Bullosa Research Association (DEBRA U.K.) and Action Research, as well as a Butterfield Award from the Great Britain Sasakawa Foundation, promoting collaborative medical research between British and Japanese institutions.
PY - 2003/3/1
Y1 - 2003/3/1
N2 - 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.
AB - 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.
KW - Alternative splicing
KW - Genodermatosis
KW - Hyalinosis cutis et mucosae
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U2 - 10.1046/j.1523-1747.2003.12073.x
DO - 10.1046/j.1523-1747.2003.12073.x
M3 - Article
C2 - 12603844
AN - SCOPUS:0037338135
SN - 0022-202X
VL - 120
SP - 345
EP - 350
JO - Journal of Investigative Dermatology
JF - Journal of Investigative Dermatology
IS - 3
ER -