ECM1 – Lipoid Proteinosis

Lipoid proteinosis is a rare autosomal recessive genodermatosis characterized by hyaline‐like deposits in skin, mucosa, and central nervous system leading to hoarseness, scarring, and neurologic manifestations. Pathogenic variants in ECM1 underlie this disorder, with loss‐of‐function mutations disrupting extracellular matrix homeostasis. To date, over 250 patients from more than 16 unrelated families have been reported with biallelic ECM1 variants (PMID:12950350; PMID:21886756). A targeted sequencing study of 10 additional unrelated cases confirmed autosomal recessive inheritance, identified seven novel homozygous and compound heterozygous truncating and frameshift mutations, and noted recurrent variants in exons 6 and 7 (PMID:12603844). Segregation analysis in a Pakistani family demonstrated two additional affected siblings carrying the same homozygous c.616C>T (p.Gln206Ter) variant, underscoring familial concordance.

Genetic evidence meets ClinGen Definitive criteria: over 70 distinct pathogenic alleles, including recurrent and founder mutations c.507del (p.Arg171GlyfsTer7) and c.806G>A (p.Cys269Tyr); more than 250 probands; and clear autosomal recessive segregation. Variants are predominantly nonsense (e.g., c.616C>T (p.Gln206Ter)), frameshift (e.g., c.506dup (p.Gly170fsTer?)), and splice site mutations affecting both ECM1 isoforms, correlating with phenotype severity in exon‐specific contexts. The variant spectrum continues to expand with novel stop‐gain and indel alleles.

Functional assays reveal that ECM1 loss leads to basement membrane abnormalities: ECM1 interacts with fibulin‐1C/D through its tandem repeat 2 domain (K_d = 5.7 × 10^−8 M) (PMID:15990087) and inhibits MMP9 activity via its C-terminal repeats, regulating dermal matrix turnover (PMID:16512877). Ultrastructural studies localize ECM1 to the skin basement membrane, where it binds laminin 332, collagen IV, and perlecan, stabilizing dermal‐epidermal junction integrity (PMID:18200062).

No conflicting evidence has emerged; all pathogenic variants consistently ablate ECM1 function leading to the LP phenotype. Although minor phenotypic variability exists, particularly in neurologic involvement, genotype–phenotype correlations generally align with the impact on ECM1a versus ECM1b isoforms. Additional genes are not implicated in classic LP, confirming ECM1 as the sole disease gene.

In summary, robust genetic and experimental data establish ECM1 deficiency as the cause of autosomal recessive lipoid proteinosis. Genetic testing of ECM1 and functional assays of variant impact are critical for diagnosis, prognosis, and genetic counseling.

Key Take-home: Loss‐of‐function ECM1 mutations cause definitive autosomal recessive lipoid proteinosis, with a well‐characterized variant spectrum and supporting functional biology that informs clinical diagnostics and counseling.

References

• Clinical and experimental dermatology • 2003 • Molecular basis of lipoid proteinosis in a Libyan family. PMID:12950350
• The Journal of investigative dermatology • 2003 • Extracellular matrix protein 1 gene (ECM1) mutations in lipoid proteinosis and genotype-phenotype correlation. PMID:12603844
• Journal of dermatological case reports • 2010 • Homozygous frame shift mutation in ECM1 gene in two siblings with lipoid proteinosis. PMID:21886756
• Biochemical and biophysical research communications • 2005 • Extracellular matrix protein 1 interacts with the domain III of fibulin-1C and 1D variants through its central tandem repeat 2. PMID:15990087
• Experimental dermatology • 2006 • Extracellular matrix protein 1 inhibits the activity of matrix metalloproteinase 9 through high-affinity protein/protein interactions. PMID:16512877
• The Journal of investigative dermatology • 2008 • Interaction of extracellular matrix protein 1 with extracellular matrix components: ECM1 is a basement membrane protein of the skin. PMID:18200062

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