TMEM251 expression and protein domains
Analyses of human expressed sequence tag (EST) data suggested that both
the long isoform and the short isoform are expressed in various tissues,
with the short isoform preferentially expressed in the brain as compared
to the long isoform. We obtained transcripts for both isoforms ofTMEM251 from blood, which was the only source of human RNA
available to us. We were able to amplify Tmem251 from cDNA
libraries mouse tissues including heart, brain, liver and kidney. In
zebrafish, higher expression of tmem251 mRNA is detected in the
axis at early somitogenesis as compared to other regions starting from
one cell to pectoral fin stage.(Thisse & Thisse, 2014) Tmem251is also expressed in ovine muscles and is upregulated in skeletal
muscles of Callipyge lambs.(Vuocolo et al., 2007)
TMEM251 has a conserved domain of unknown function (DUF4583)
corresponding to amino acids 40 to 167 (NP_001092091.1) in the 169
amino acid protein in the human long isoform (Figure 3B). The short
isoform lacks 35 amino acids from the N-terminal (Figure 3B). TMEM251 is
predicted to be a transmembrane protein with two alpha helices (Figure
3D). No signal peptide was detected in the protein sequence by
computational analyses. The N-terminal and C-terminal are predicted to
face the lumen. ProtFun 2.2 analyses predicted TMEM251 to be a
transporter with high odds of 4.139.
The missense variant p.(Arg45Trp) (NP_001092091.1), or p.(Arg7Trp)
(NP_056491.1) affects an amino acid located close to the first
transmembrane segment at the amino terminal of both isoforms of the
protein. The variant is predicted to result in the incorporation of the
mutated amino acid tryptophan inside the membrane as part of the first
transmembrane segment making it unavailable in the lumen (Figure 3D).
This effect is similar to that predicted for an arginine to tryptophan
variant pathogenic allele of TMEM230 in Parkinson’s disease.(Deng et
al., 2016) The frameshift variant c.215dupA;p.(Tyr72Ter) is predicted to
truncate the protein in the non-transmembrane segment located between
the two transmembrane regions which may give rise to a shortened protein
which may be unstable. No protein may be produced at all if
nonsense-mediated decay of the mutant transcript occurs.