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Self-healing collodion baby: a dynamic phenotype explained by a particular transglutaminase-1 mutation
Michael Raghunath1, Hans-Christian Hennies, Bijan Ahvazi
1Department of Dermatology, University Hospital, Münster, Germany.
Insights
Self-healing collodion baby (SHCB) is a rare skin condition. Genetic mutations in transglutaminase 1 (TGM1) were identified in siblings, explaining the condition
Area of Science:
- Genetics
- Dermatology
- Biochemistry
Background:
- Congenital ichthyosis encompasses a group of rare genetic skin disorders.
- Self-healing collodion baby (SHCB) is a subtype characterized by spontaneous resolution of collodion membranes and ichthyosis.
- Epidermal transglutaminase 1 (TGM1) plays a crucial role in skin barrier formation.
Purpose of the Study:
- To investigate the genetic basis of the self-healing collodion baby phenotype in affected siblings.
- To elucidate the functional impact of identified transglutaminase 1 mutations on enzyme activity.
Main Methods:
- Genetic sequencing to identify mutations in the transglutaminase 1 gene.
- Molecular modeling to predict the structural and functional consequences of mutations.
- Biochemical assays to assess the activity of mutant transglutaminase 1 proteins.
Main Results:
- Two siblings with SHCB were found to be compound heterozygous for transglutaminase 1 (TGM1) mutations: G278R and D490G.
- Molecular modeling and biochemical assays indicated significantly reduced activity for the G278R mutant.
- The D490G mutation was associated with water molecule chelation, locking the enzyme in an inactive trans conformation in utero, which resolves postnatally, restoring partial activity.
Conclusions:
- Compound heterozygous mutations in the transglutaminase 1 gene explain the self-healing collodion baby phenotype.
- The identified TGM1 mutations lead to altered enzyme conformation and activity, particularly during fetal development.
- The postnatal resolution of the skin condition is attributed to the enzyme's predicted isomerization to a partially active cis form after birth.
Abstract:
Spontaneous healing with no or only very mild ichthyosis distinguishes the "self-healing collodion baby" from other congenital ichthyoses. In two self-healing collodion baby siblings with markedly diminished epidermal transglutaminase 1 activity we found the compound heterozygous transglutaminase 1 mutations G278R and D490G. Molecular modeling and biochemical assays of mutant proteins under elevated hydrostatic pressure suggest significantly reduced activity in G278R and a chelation of water molecules in D490G that locks the mutated enzyme in an inactive trans conformation in utero. After birth these water molecules are removed and the enzyme is predicted to isomerize back to a partially active cis form, explaining the dramatic improvement of this skin condition.