Mutations in KDSR Cause Recessive Progressive Symmetric Erythrokeratoderma

Area of Science:

• Genetics
• Dermatology
• Biochemistry

Background:

• Genetic discoveries advance understanding of epidermal function and inherited skin disorders.
• Ceramide synthesis is crucial for skin barrier integrity.

Purpose of the Study:

• Identify genetic causes of a novel recessive Mendelian disorder within the erythrokeratoderma spectrum.
• Characterize the molecular mechanisms underlying the disorder and evaluate therapeutic interventions.

Main Methods:

• Exome and genome sequencing to identify mutations in KDSR (3-ketodihydrosphingosine reductase).
• cDNA sequencing and splicing assays to confirm pathogenic mutations.
• Immunohistochemistry and yeast complementation to assess enzyme function.
• Clinical evaluation and treatment response to isotretinoin.

Main Results:

• Identified mutations in KDSR as the cause of a new progressive symmetric erythrokeratoderma spectrum disorder.
• Discovered a large pathogenic inversion and splice-site mutations leading to exon skipping and impaired KDSR function.
• Demonstrated significant clinical improvement with systemic isotretinoin therapy.

Conclusions:

• KDSR mutations disrupt ceramide synthesis, leading to a severe inherited skin disorder.
• Genome sequencing is crucial for identifying complex mutations like inversions.
• Isotretinoin shows promise for treating this KDSR-associated erythrokeratoderma by modulating ceramide pathways.