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.

Importance of Extracellular Matrix Protein 1 (ECM1) in Maintaining the Functional Integrity of the Human Skin

“…Extracutaneous features including epilepsy, mental retardation, migraine and psychiatric abnormalities were equally found in patients lacking only ECM1a compared with patients lacking both transcripts [26][27][28][29][30]. These findings favor the hypothesis that the isoforms containing exon 7 (ECM1a/c) are of more fundamental biological importance than ECM1b [23,27]. However, individuals sharing the same genetic background and an identical mutation in ECM1 can present a different phenotype during disease progression, pointing out the heterogeneity of the disease [31].…”

“…From a clinical perspective, patients with mutations outside exon 7, compared to those with mutations inside exon 7, have a similar clinical presentation, but with a more severe phenotype for respiratory and skin manifestations of LiP. Extracutaneous features including epilepsy, mental retardation, migraine and psychiatric abnormalities were equally found in patients lacking only ECM1a compared with patients lacking both transcripts [26][27][28][29][30]. These findings favor the hypothesis that the isoforms containing exon 7 (ECM1a/c) are of more fundamental biological importance than ECM1b [23,27].…”

“…Mutations in ECM1 are causative for LiP, an autosomal recessive disorder, also known as Urbach-Wiethe disease or hyalinosis cutis et mucosae (OMIM 247100) [26,27]. LiP is mainly a mucocutaneous disorder characterised by laryngeal infiltration leading to hoarseness, generalised thickening and scarring of skin and mucosae, beaded eyelid papules, waxy yellow skin papules and nodules.…”

“…LiP is mainly a mucocutaneous disorder characterised by laryngeal infiltration leading to hoarseness, generalised thickening and scarring of skin and mucosae, beaded eyelid papules, waxy yellow skin papules and nodules. Extracutaneous features including epilepsy, mental retardation, migraine and psychiatric abnormalities are also described [26][27][28][29][30]. Increased skin scaling and infiltration occur in regions exposed to mechanical friction including elbows, hands and knees [23].…”

“…Up to 4 missense and 6 nonsense mutations occur in the alternatively spliced exon 7, which leads to the ablation of the ECM1a/c transcript, but not the shorter ECM1b which lacks this exon (Fig. 1B) [22,23,27,[31][32][33]. Outside exon 7, most other mutations are found in exon 6 (missense and nonsense mutations) [22,27,32,[34][35][36]39] with the 507delT mutation existing as a hotspot, because of its appearance in patients with different genetic backgrounds [27,37,38].…”