CERS3 Gene

The CERS3 gene (CERS3 is the acronym for Ceramide Synthase 3) is a protein-coding gene laoclated on chromosome 15q26.3. Alternative splicing results in multiple transcript variants encoding different isoforms.

Diseases associated with CERS3 include.

Ichthyosis, Congenital, Autosomal Recessive 9 (Autosomal recessive congenital ichthyosis with mutation in CERS3).

Mutations in CERS3 can lead to a specific loss of ceramides in keratinocytes. In finally differentiating keratinocytes, this loss mainly affects ceramides with very long acyl chains from C26 to C34 (Eckl KM et al. 2013). Analysis of reconstructed patient skin shows disruption of epidermal differentiation with earlier maturation and impaired epidermal barrier function.

Mutations in this gene are also associated with male fertility disorders.

The CERS3 gene belongs to the ceramide synthase gene family. The protein enzymes encoded by this gene family, the ceramide synthases regulate sphingolipid synthesis by catalyzing the formation of ceramides from sphingoid bases and acyl-CoA substrates.

Ceramide synthase 3 (CerS3) is synthesized in skin and testis (Eckl KM et al. 2013). It catalyzes the formation of ceramide from sphinganine and acyl-CoA substrates, with high selectivity for very long (C22:0-C24:0) and ultra-long chains (more than C26:0) as acyl donors. The enzyme is critical for the synthesis of these ultralong chain ceramides in the epidermis. These prove to be necessary to maintain epidermal lipid homeostasis and terminal differentiation. Ultralong-chain ceramides are important for the epidermis to form a protective barrier against the environment. Ceramide synthase 3 is further also involved in the modification of lipid structures required for spermatogenesis.

Casuistics: Radner FPet al (2013 reported four patients from three consanguineous Tunisian families with skin, eye, cardiac and skeletal anomalies that have a homozygous linked gene deletion syndrome on chromosome 15q26.3. Genome-wide SNP genotyping revealed a homozygous microdeletion affecting two coding genes(ADAMTS17, CERS3) and eliminating a sequence for a long noncoding RNA (FLJ42289) in all affected individuals. Mutations in ADAMTS17 are associated with autosomal recessive Weill-Marchesani syndrome in humans and dogs (ophthalmic, cardiac, and skeletal abnormalities). Mutations a CERS3 (ceramide synthase 3) are associated with nonsyndromic ARCI. Functional analysis of patients' skin and keratinocytes differentiated in vitro showed that mutations in CERS3 lead to a disturbed sphingolipid profile with decreased amounts of epidermis-specific very long-chain ceramides, which impairs epidermal differentiation (Radner FPet al. 2013).

Eckl KM et al (2013) diagnosed a homozygous missense mutation in the CERS3 gene. Phenotypically, it revealed autosomal recessive congenital ichthyosis characterized by collodion membranes at birth, generalized scaling of the skin, and mild erythroderma.

1. Eckl KM et al (2013) Impaired epidermal ceramide synthesis causes autosomal recessive congenital ichthyosis and reveals the importance of ceramide acyl chain length. J Invest Dermatol 133:2202-2211.
2. Ennouri M et al. (2022) Clinical and genetic investigation of ichthyosis in familial and sporadic cases in south of Tunisia: genotype-phenotype correlation. BMC Med Genomics 15:4.
3. Radner FPet al. (2013) Mutations in CERS3 cause autosomal recessive congenital ichthyosis in humans. PLoS Genet 9:e1003536.