Molecular Characteristics
RTTN encodes rotatin, whose deficiency in mice was shown to cause abnormal development of left-right asymmetry, randomized heart tube looping, and abnormal differentiation of the neural tube. RTTN likely acts upstream of most left-right asymmetry proteins, including nodal, lefty, and PITX2 and may play a role in the development of cilia. RTTN-knockdown experiments showed an abnormal shortening of the cilia, which may explain RTTN-related left-right asymmetry. The connection to microcephalic primordial dwarfism is likely related to its ciliary function although the exact mechanism remains unknown.
Mutations and pathophysiology
RTTN is located at 18q22.2. One study identified an intronic variant, c.2885+8A >G [p.Ser963*] in RTTN exon 23, which creates a cryptic slice donor and leads to premature truncation. The study, which linked the mutations to microcephalic primordial dwarfism with a distinctive brain phenotype (see Clinical Characteristics), also identified c.3190A >C, which predicts an amino acid substitution, p.Lys1064Gln, and biallelic mutations affecting exons 13 and 43 (c.1732G >C [p.Ala578Pro] and c.5750A >G [p.Asp1917Gly]) (GenBank: NM_173630.3).
Another study identified a missense mutation in exon 22 of RTTN, c.2796A>T (p.Leu932Phe) and c.80G>A in exon 2 of RTTN (p.Cys27Tyr) (RefSeq accession number NM_173630.3). These mutations resulted in autosomal-recessive polymicrogyria. Abnormally short, dysmorphic cilia were also noted in the primary fibroblasts of the affected individuals.