Type of mutations
The great majority of tested individuals with hereditary mucoepithelial dysplasia carries a recurrent heterozygous c.1579C>T, p.Arg527Cys (transcript NM_004176.5) pathogenic variant in the SREBF1gene (annotated as c.1669C>T, p.Arg557Cys in early reports). Other rarely identified disease-causing heterozygous variants include p.Arg527His, p.Asn528del, and p.Leu530Pro.
Genetic testing
The recurrent pathogenic variant c.1579C>T is detected by sequencing analysis of the SREBF1gene.
Possible molecular diagnostic approaches to confirm the diagnosis in a patient with clinical suspicion of hereditary mucoepithelial dysplasia include:
• Performing SREBF1exon 8 Sanger sequencing, if the clinical suspicion of hereditary mucoepithelial dysplasia is high.
• Performing Sanger sequencing of the entire SREBF1gene if exon 8 sequence is wild type.
Parents’ clinical evaluation and targeted genetic testing of identified variants in the SREBF1gene is recommended to verify if the pathogenic variant identified in the proband was inherited or occurred de novo.
Suspected pathophysiologic mechanism
The SREBF1gene codes for the Sterol Regulatory Element-Binding Protein 1 (SREBP-1), a transcription factor that regulates lipid homeostasis, including fatty acid synthesis and cholesterol metabolism. Loss-of-function mutations in SREBF1lead to impaired lipid metabolism which in turn results in disturbed differentiation of epidermal structures. A gain-of-function SREBF1nonsense variant, c.1289C>A (p.Ser430*), which produces a SREBP-1 protein preferentially located at the nucleus, in contrast to wild-type SREBP-1 which is mainly localized in the cytoplasm, was associated with generalized skin hyperpigmentation and congenital cataracts.
SREBF1