Homozygous frame shift mutation in ECM1 gene in two siblings with lipoid proteinosis

Abstract

Background: The extracellular matrix protein 1 (ECM1) is a glycoprotein, expressed in skin and other tissues. Loss-of-function mutation in ECM1 causes a rare autosomal recessive disorder called lipoid proteinosis. Lipoid proteinosis is presented by varying degrees of skin scars, beaded papules along the eyelid margins, variable signs of hoarseness of voice and respiratory disorders. More than 250 cases of this disorder have been described in the literature, but occurrence of lipoid proteinosis in siblings is very rare. This study was designed to investigate the possible mutation causing lipoid proteinosis in a Pakistani family and to elaborate the scope of possible genetic changes, causing the genodermatosis in Pakistan.Main observations: In this study, two siblings (12 and 9-years sisters) were presented with scaly itchy lesions on whole body, hoarse voice and macroglossia. Their deceased father had similar clinical manifestations but mother and younger brother were unaffected. Blood samples from clinically affected and unaffected family members were collected with informed consent. The coding region of ECM1 gene containing 10 exons were amplified and sequenced.Both the affected siblings were shown to have homozygous frame shift mutation by deletion of the nucleotide T at 507, codon 169, exon 6. This resulted in a frame shift from codon 169 and appearance of a premature stop codon at 177, causing formation of a mutated protein (176 amino acids) instead of normal ECM1 protein (540 amino acids).Conclusion: A case of homozygous 62-bp insertion in ECM1 gene causing lipoid proteinosis has been reported in another Pakistani family. The current study presents a homozygous frame shift mutation supporting an unusual function of ECM1 protein and broadens the spectrum of disease-linked mutations in this rare case of genodermatosis in this region.

Pathogenetic mechanism of lipoid proteinosis caused by mutation of the extracellular matrix protein 1 gene

“…Agarose gel electrophoresis was performed using standard procedure; 5 µl PCR products were mixed with 1 µl loading buffer (6X) and loaded into 0.8% agarose gel. The electrophoresis was performed in a 120 V electrical field for 10 min as previously described (19).…”

A Novel Association of the Additional Intracranial Calcification in Lipoid Proteinosis: A Case Report

“…No definitive age, sex or race predilections exist. There is a documented autosomal recessive inheritance as there is usually a history of consanguinity among the unaffected parents [9]. A mental sub normality is seen only when it is transmitted by autosomal dominant inheritance due to the mutant genes [3].…”

Single nucleotide substitution mutations and polymorphisms in ECM1 gene in lipoid proteinosis in siblings of a Pakistani family

“…A number of recent genetic studies reported the involvement of homozygous frame shift, missense, nonsense and single nucleotide substitution, deletion and insertion mutations in ECM1 gene LP which is located on chromosome 1q21.2 (Salih et al, 2011;Samdani et al, 2010;Kumar et al, 2009;Nasir et al, 2009). About 300 cases of LP have been so far reported.…”

“…In patient 2, at the same location of exon 8, polymorphism of nucleotide G to A (G/A) was observed ( Figure 6), but this does not cause any change in the coded amino acid. Earlier, a case of homozygous 62-bp insertion (Nasir et al, 2009) and a case of homozygous frame shift mutation leading to premature termination of ECM1 protein causing LP (Samdani et al, 2010) have been reported in Pakistani families.…”