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.