J Clin Neurol.  2014 Jan;10(1):64-68.

Clinical and Molecular Study of the Extracellular Matrix Protein 1 Gene in a Spanish Family with Lipoid Proteinosis

• Mondejar R
• Garcia-Moreno JM
• Rubio R
• Solano F
• Delgado M
• Garcia-Bravo B
• Rios-Martin JJ
• Martinez-Mir A
• Lucas M

Abstract

BACKGROUND
Lipoid proteinosis (LP) is a rare autosomal recessive disorder characterized by a hoarse voice, variable scarring, and infiltration of the skin and mucosa. This disease is associated with mutations of the gene encoding extracellular matrix protein 1 (ECM1).
CASE REPORT
This was a clinical and molecular study of a new case of LP with a severe phenotype. A 35-year-old female born to nonconsanguineous parents developed dermatological and extracutaneous symptoms in her 9th month of life. The neurological abnormalities of the disease began to appear at the age of 19 years. Computed tomography revealed cranial calcifications.
CONCLUSIONS
The diagnosis of LP was confirmed by histopathological findings and direct sequencing of ECM1. A new homozygous nonsense mutation was identified in exon 7 of ECM1, c.1076G>A (p.Trp359*). This mutation was not detected in 106 chromosomes of healthy individuals with a similar demographic origin. Microsatellite markers around ECM1 were used to construct the haplotype in both the parents and the patient. Reports on genotype-phenotype correlations in LP point to a milder phenotype in carriers of missense mutations in the Ecm1a isoform, whereas mutations in the Ecm1b isoform are thought to be associated with more severe phenotypes. The present findings in a Spanish patient carrying a truncating mutation in exon 7 revealed complete dermatological and neurological manifestations.

Keyword

ECM1 gene; lipoid proteinosis; mutation; exon 7; phenotype

MeSH Terms

Adult
Cicatrix
Codon, Nonsense
Diagnosis
Exons
Extracellular Matrix*
Female
Genetic Association Studies
Haplotypes
Humans
Microsatellite Repeats
Mucous Membrane
Mutation, Missense
Neurologic Manifestations
Parents
Phenotype
Skin
Voice
Codon, Nonsense

Figure

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  Fig. 1 A and B: Axial brain computed tomography image showing bilateral and symmetric calcifications of the mesial temporal lobes (amygdala complex, uncinate, hippocampi, and parahippocampal giri). C: Axial brain GRE T2*-weighted MRI image (TR; TE) depicting bilaterally hypointense lesions in both amygdaloid bodies. D: Coronal brain T2*-weighted MRI image showing the same horn-shaped amygdaloid lesions. E: Homogeneous eosinophilic material was deposited around the sweat coils and capillaries, with the perineurium of a nerve also being affected (hematoxylin and eosin stain, ×200). F: The deposited material stained very strongly with periodic acid Schiff (diastase-resistant; ×200).

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  Fig. 2 Identification of the c.1076G>A transversion in ECM1 in exon 7. (A) Homozygous mutation in the patient, (B) wild-type sequence, and (C) restriction fragment analysis with NlaIII. The c.1076G>A transversion causes loss of the restriction site. Fragments of digested amplicons of homozygous carriers (-/-), heterozygous carriers (+/-), and the wild-type control (+/+) were separated on a 1.5% agarose gel. The PCR product was not digested in the homozygous patient, and a single band of 439 bp was detected. MW refers to the 50-bp molecular-weight marker. D: The mutation causes a premature termination codon that predicts a truncated protein. E: Pedigree of the family with LP.

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