Unique JEB mutations explain wide clinical variability, study shows
Little known about link between specific gene mutations, symptoms
Among a group of people with junctional epidermolysis bullosa (JEB), nearly all genetic mutations associated with the condition were unique, which may explain the wide range of symptom presentation and severity among patients, a study reported.
Researchers noted that accurately predicting outcomes is challenging because some cases were less severe than expected based on genetic defects.
The study, “Genotype-phenotype correlation in Junctional Epidermolysis Bullosa: signposts to severity,” was published in the Journal of Investigative Dermatology.
JEB is a rare moderate-to-severe form of epidermolysis bullosa, a group of disorders marked by fragile skin that easily blisters and tears. This form of the disease typically appears at birth or in early infancy, with blistering over large areas of the body.
Mutations in COL17A1 gene can cause an intermediate form of JEB
Most cases of JEB are caused by gene mutations that disrupt the production of laminin 332, a protein that helps strengthen skin by holding its layers together. In some cases, mutations in COL17A1 gene, which encodes part of type XVII collagen that gives structure and strength to connective tissues, cause an intermediate form of JEB.
There are two main clinical JEB subtypes: a severe form, in which children do not survive beyond the first few years of life; and an intermediate form, whereby patients live into adulthood but with varying degrees of severity.
However, because of its rarity, little is known about the connection between specific gene mutations and clinical characteristics — a relationship referred to as genotype-phenotype correlation.
To address this knowledge gap, a team led by researchers at the University of Birmingham in the U.K. examined the genetic and clinical findings of a group of 17 JEB patients.
Seven of the patients had severe JEB (all had died), and nine had intermediate JEB (all living). One patient (who had died) had an extremely rare JEB subtype called laryngo-onycho-cutaneous syndrome, which affects the voicebox, fingernails, and toenails, as well as the skin.
A total of 21 mutations was detected across all patients, with those in the LAMB3 gene, which encodes part of laminin 332, accounting for the majority (57%). Other mutations were found in the COL17A1 gene, as well as genes that encode other parts of laminin 332, including LAMA3 and LAMC2.
The team noted that few individuals had the same mutation (genotype), with 18 of the 21 mutations being unique. Among them, seven had yet to be reported in the literature. All four patients with COL17A1 mutations had intermediate JEB.
Consistent with the LAM gene mutational analysis, there were no signs of laminin 332 in skin samples collected from severe JEB cases and low levels in intermediate JEB cases. This was assessed by immunofluorescence mapping, a technique that uses antibodies to detect stable laminin 332 in tissues.
5 splicing variants among 21 mutations detected
Among the 21 mutations detected, five were considered splicing variants in the LAMB3 gene, which affects the processing of messenger RNA, the intermediate molecule between genes and the proteins they produce.
In two severe JEB cases, splice site mutations were likely to produce no functional laminin 332, which also correlated with no signs of the protein using immunofluorescence mapping. In the remaining three intermediate JEB cases, splice mutations led to some functional laminin 332, as indicated by reduced immunofluorescence signals.
Among the nine living individuals with intermediate JEB, between 0% and 60% of the skin was affected. The nails of all of these patients were affected, with assessment scores ranging from 2.5 to 5 (all nails lost).
In more than half of the cases, there was eye involvement, chronic wounds, indented (atrophic) scarring, tooth damage or loss, oral ulcers, hair loss (alopecia), anemia (low red blood cells), and below-normal weight.
Less common signs (less than half) included voice box involvement, low blood albumin levels, a potential sign of liver or kidney problems, and granulation tissue, new connective tissue that forms during the healing process.
“Different phenotypes within the intermediate JEB subtype were highlighted by variation in the presence and severity of characteristics,” the researchers wrote.
Still, the team noted that the description of clinical characteristics in this study was limited due to the examination at one point in time. As such, assessments over time will allow a more accurate description of the disease course related to specific mutations.
“Accurate genotype-phenotype correlation has important clinical implications for JEB patients,” the researchers concluded. “Accurate predictions are challenging as a number of cases have a phenotype that is less severe than expected from their genetic defect.”
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