TMEM263: a novel candidate gene implicated in human autosomal recessive severe lethal skeletal dysplasia

Abstract

Introduction Skeletal dysplasia is a common, clinically and genetically heterogeneous disorder in the human population. An increasing number of different genes are being identified causing this disorder. We used whole exome sequencing (WES) for detection of skeletal dysplasia causing mutation in a fetus affected to severe lethal skeletal dysplasia. Patient Fetus was assessed by ultrasonography in second trimester of pregnancy. He suffers from severe rhizomelic dysplasia and also pathologic shortening of ribs. WES was applied to finding of causal mutation. Furthermore, bioinformatics analysis was performed to predict mutation impact. Results Whole exome sequencing (WES) identified a homozygous frameshift mutation in the TMEM263 gene in a fetus with severe lethal skeletal dysplasia. Mutations of this gene have been previously identified in dwarf chickens, but this is the first report of involvement of this gene in human skeletal dysplasia. This gene plays a key role in the growth hormone signaling pathway. Conclusion TMEM263 can be considered as a new gene responsible for skeletal dysplasia. Given the complications observed in the affected fetus, the mutation of this gene appears to produce much more intense complications than that found in chickens and is likely to play a more important role in bone development in human.

Tmem263 deletion disrupts the GH/IGF-1 axis and causes dwarfism and impairs skeletal acquisition

“…It is not known whether the dwarf chicken with a loss-of-function mutation in TMEM263 is also insensitive to GH stimulation. To date, there is only one documented case of a loss-of-function mutation in T MEM263 , and it was associated with severe skeletal dysplasia in a fetus ( Mohajeri et al, 2021 ). Because pregnancy was terminated before full term, it is unclear whether this mutation is compatible with postnatal survival and its impact on the severity of postnatal growth retardation.…”

“…Intriguingly, a nonsense mutation (Trp59*) that truncates the TMEM263 protein is linked to dwarfism in chicken ( Wu et al, 2018 ), although it is unclear if this mutation directly causes dwarfism. More recently, a two nucleotide deletion that causes a frameshift and premature termination in TMEM263 was implicated as a candidate gene for a severe case of autosomal-recessive skeletal dysplasia in a fetus ( Mohajeri et al, 2021 ). Apart from this limited information, little is known about TMEM263 and its function.…”

Tmem263 deletion disrupts the GH/IGF-1 axis and causes dwarfism and impairs skeletal acquisition

“…It is not known whether the dwarf chicken with a loss-of-function mutation in TMEM263 is also insensitive to GH stimulation. To date, there is only one documented case of a loss-of-function mutation in T MEM263 , and it was associated with severe skeletal dysplasia in a fetus (8). Because pregnancy was terminated before full term, it is unclear whether this mutation is compatible with postnatal survival and its impact on the severity of postnatal growth retardation.…”

“…Intriguingly, a non-sense mutation (Trp59*) that truncates the TMEM263 protein is linked to dwarfism in chicken (7), although it is unclear if this mutation directly causes dwarfism. More recently, a two nucleotide deletion that causes a frameshift and premature termination in TMEM263 was implicated as a candidate gene for a severe case of autosomal recessive skeletal dysplasia in a fetus (8). Apart from this limited information, little is known about TMEM263 and its function.…”

Nutrient-Response Pathways in Healthspan and Lifespan Regulation

“…These results link a nutrient and possible direct, or indirect [133], mTOR inhibitor, in possible agerelated metabolic pathologies. In another diet-related EWAS study, blood-based differential methylomes comparing responders and non-responders to vitamin K1 supplementation (identified in a 3-year supplementation test) revealed multiple regions with previously unknown relationships to Vitamin K1 absorption and metabolism, such as at the TMEM263 locus [135], coding a gene previously reported to be involved in skeletal dysplasia [136]. Finally, in another study, differential methylome was examined after bariatric surgery.…”