A synonymous single nucleotide variant on the FAM20C gene causes non-lethal Raine syndrome.

Area of Science:

• Genetics
• Molecular Biology
• Biochemistry

Background:

• Raine syndrome (RNS) is a severe, autosomal recessive neonatal osteosclerotic bone dysplasia.
• Biallelic mutations in the FAM20C gene, encoding a Golgi serine/threonine kinase, cause RNS.
• Nonlethal forms of RNS have been recently identified, suggesting diverse genetic mechanisms.

Purpose of the Study:

• To investigate the genetic basis of a nonlethal form of Raine syndrome in a Turkish family.
• To elucidate the molecular mechanism underlying the identified FAM20C variant in RNS pathogenesis.

Main Methods:

• Exome sequencing was performed on three affected family members.
• FAM20C gene analysis, including mRNA (cDNA) sequencing, identified a novel splice-site variant.
• Functional studies assessed protein localization, secretion, and dimerization.

Main Results:

• A homozygous synonymous variant (c.1071A>G) in FAM20C was identified, leading to a 12 amino acid insertion due to aberrant splicing.
• The variant protein retained its ability to dimerize but failed to localize correctly to the Golgi apparatus.
• Impaired Golgi localization and reduced secretion of the variant FAM20C protein were observed.

Conclusions:

• The identified FAM20C splice-site variant causing a 12 amino acid insertion is responsible for the nonlethal RNS phenotype in this family.
• This finding provides mechanistic insight into RNS pathogenesis, highlighting the critical role of FAM20C protein localization and secretion.
• The study expands the spectrum of FAM20C mutations associated with RNS and underscores the importance of splice-site analysis.