Discussion
We have identified two novel homozygous variants in TMEM251 as
the likely cause of a complex progressive skeletal disorder leading to
severe short stature and early mortality in two unrelated families. Our
findings indicate that TMEM251 may have a metabolic role. The
clinical course of disease in both families was suggestive of a
metabolic multisystemic disorder which was supported by the widespreadTMEM251 expression pattern. The affected individuals in the two
families had striking phenotypic similarities to patients with
mucolipidosis and mucopolysaccharidosis(Bonafe et al., 2015)
specifically to Mucolipidosis II/III based on patient characteristics of
short stature, dysostosis multiplex, severe physical handicap, facial
dysmorphology and distended abdomens (Dr. Leroy, personal
communication). However, variants in the causative genes for these
disorders (GNPTAB or GNPTG) were excluded as cause of the
phenotype. Interestingly, both GNPTAB and GNPTG localize to Golgi
complex, as is the case for TMEM251. Studies are required to test
whether the three proteins participate in the same cellular pathways.
The unavailability of patients’ cells for RNA or protein expression
studies hinders the evaluation of variants effects in vivo . Brain
and cardiac imaging studies in the Iranian patient suggested the
pathogenic variants in this gene could be responsible for cardiac and
brain abnormalities. The unavailability of abdominal and cardiac imaging
and laboratory examinations for the Pakistani family however, precluded
further investigations to unravel organ abnormalities, including
hepatosplenomegaly and cardiac anomalies.
Our results indicate that the p.(Arg45Trp) variant could be a functional
null allele while the p.(Tyr72Ter) may also be a loss of function
allele. The decreased localization of p.(Arg45Trp) TMEM251 to plasma
membrane as well as to the Golgi complex may be due to improper folding
of the protein. This may halt its incorporation into the membranes or
cause degradation of the mutant TMEM251. The reduction in chondrogenic
marker Col2a1 after siRNA-induced knockdown of Tmem251 in
rat primary chondrocytes suggests that TMEM251 may play a role in the
differentiation of chondrocytes and thus have an important function in
the development of cartilage and bones. Future studies of animal models
with Tmem251 variants could elucidate the role of the encoded
protein in skeletogenesis in more detail.
In conclusion, our findings implicate homozygous TMEM251 variants
as the genetic cause of a severe skeletal dysplasia with features of a
metabolic disorder. Identification of additional affected individuals
due to TMEM251 variants will delineate the full spectrum of the
disorder and expand phenotypic manifestations as well as the molecular
mechanisms involved in the disease course. Continued research
will elucidate the role of TMEM251 in human physiology.