Rotatin

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OMIM Number

610436

Gene Map Locus
18q22.2

Description

Rotatin encodes a protein that is localized at the ciliary basal bodies in human fibroblast cells.  While the exact function of Rotatin is yet to be elucidated, it is predicted to play a key role in early developmental processes such as axial rotation and left-right specification by maintaining ciliary structure.  It may also be involved in notochord development.  Mouse studies of homozygous RTTN null embryos have found to result in randomized heart looping, delayed neural tube closure, axial rotation failure and eventually, embryonic death.  This further confirms the importance of Rotatin in embryonic development.

Mutations in RTTN have been associated with MSSP, a syndrome characterized by microcephaly, primordial dwarfism and polymicrogyria.  

Molecular Genetics

The RTTN gene is located on the long arm of chromosome 18 and is made up of 54 exons.  It encodes a 246 kDa protein that is made of 2226 amino acids.  Several homozygous and compound heterozygous mutations in the RTTN gene have been associated with MSSP.  These include multiple transversions and transitions resulting in amino acid substitutions at highly conserved residues and an insertion (c.2885+8A-G) resulting in a premature stop codon (S963X).  

Epidemiology in the Arab World

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Other Reports

Saudi Arabia

Shamseldin et al. (2015) reported on two Arab MSSP affected families.  Family 1 was a Yemeni consanguineous family with three affected siblings that showed severe short stature, microcephaly, craniofacial dysmorphism and intellectual disability.  In family 2, a 5.5-year-old Saudi Arabian boy, born to healthy consanguineous parents, was found to suffer from severe microcephaly with simple gyration, microcephalic dwarfism, and craniofacial dysmorphism.  Autozygome analysis and exome filtering for rare variants in family 1 uncovered an intronic variant c.2885+8A>G in exon 23 of the RTTN gene resulting in a premature stop codon S963X.  Analysis of the Saudi Arabian child revealed a homozygous c. 3190A>C mutation.  The parents and unaffected sisters were found to be heterozygous for the mutation.  As the affected lysine residue was conserved down to zebrafish, in-situ analysis predicted this mutation to be highly pathogenic.  Both variants were not found in 1000 Genomes, the ExAC Browser or control exomes.  Linkage analysis of families 1 and 2 revealed the only significant linkage peak to map to the RTTN gene, further confirming the association of RTTN with this disorder. 

Yemen

[See: Saudi Arabia > Shamseldin et al., 2015]

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