A new homozygous nonsense mutation inLAMA3Aunderlying laryngo-onycho-cutaneous syndrome

Abstract

Laryngo-onycho-cutaneous (LOC) syndrome is a subtype of autosomal recessive junctional epidermolysis bullosa in which there is prominent skin and mucosal granulation tissue that can lead to delayed wound healing, laryngeal obstruction and blindness. Thus far, all cases are of Punjabi ancestry and have been shown to result from a founder mutation in the LAMA3 gene, notably involving a single nucleotide insertion mutation in exon 39, which is specific to the LAMA3A (designated exon 1 of LAMA3A) and not the LAMA3B1 or LAMA3B2 isoforms. Here, we describe a new pedigree with LOC syndrome. Affected individuals (from Iran) have the characteristic clinicopathological and molecular features of LOC syndrome: prominent granulation tissue (especially affecting the eyes), normal intensity laminin-332 immunostaining at the dermal-epidermal junction, and autosomal recessive mutations in the LAMA3A-specific exon. The pathogenic mutation is a homozygous nonsense mutation, designated p.Gln57X, which just affects the laminin-α3a transcript. These findings therefore expand the molecular basis of LOC syndrome.

Novel autosomal recessive LAMA3 and PLEC variants underlie junctional epidermolysis bullosa generalized intermediate and epidermolysis bullosa simplex with muscular dystrophy in two consanguineous families

“…Mutations in one of the three laminin genes, encoding the α3 subunit ( LAMA3 ), the β3 subunit ( LAMB3 ), and the γ2 subunit ( LAMC2 ), have been reported to affect laminin‐5 expression . The LAMA3 gene encodes the laminin subunit α3 of the laminin‐5 protein, reported to cause gsJEB, giJEB and laryngo–onycho–cutaneous syndrome . In the current study, we found a homozygous nonsense variant (p.Ser3298*) causing giJEB, which affects the LG5 subdomain and leads to a truncated protein lacking the final 37 amino acids.…”

Using immunofluorescence (antigen) mapping in the diagnosis and classification of epidermolysis bullosa: a first report from Iran

“…Genetic molecular studies showed nonsense mutations in the last codon of exon 39 of the laminin α 3a ( LAMA3 ) gene (p.Gln57X) in the first family. Then we reported a new pedigree with LOC syndrome from outside of Panjabi ethnicity . While in the other family, detection of a donor splice site mutation in LAMA3 (IVS57+5G>A) was corroborative evidence in favor of non‐Herlitz JEB.…”

Challenges of the differential diagnosis between the subtypes of the junctional epidermolysis bullosa: presentation of two clinical cases

“…В 2008 г. данная нозология была внесена в классификацию БЭ как один из подтипов ПоБЭ [2]. Результаты, полученные в 2003 г., подтверждены последующими публикациями описаний пациентов с ЛОК синдромом, у которых генетическая диагностика выявила мутации в участке гена, кодирующем альфа-цепь LAMA3 [11].…”

“…При этом имеются случаи описания пациентов со смешанными проявлениями как тяжелого генерализованного ПоБЭ, так и ЛОК синдрома, у которых обнаружены сложные гетерозиготные мутации в LAMA3 и его изоформе LAMA3A [11,30].…”

“…Все подтипы ПоБЭ наследуются по аутосомно-рецессивному типу. При ПоБЭ описаны мутации в генах ламинина-332, коллагена 17-го типа, интегринов альфа-3, альфа-6, бета-4; в основном это нонсенс-мутации, делеции, мутации сайта сплайсинга [2,10,11].…”