Biallelic TMEM251 variants in patients with severe skeletal dysplasia and extreme short stature

Abstract

Skeletal dysplasias are a heterogeneous group of disorders ranging from mild to lethal skeletal defects. We investigated two unrelated families with individuals presenting with a severe skeletal disorder. In family NMD02, affected individuals had a dysostosis multiplex-like skeletal dysplasia and severe short stature (<−8.5 SD). They manifested increasingly coarse facial features, protruding abdomens, and progressive skeletal changes, reminiscent of mucopolysaccharidosis. The patients gradually lost mobility and the two oldest affected individuals died in their twenties. The affected child in family ID01 had coarse facial features and severe skeletal dysplasia with clinical features similar to mucopolysaccharidosis. She had short stature, craniosynostosis, kyphoscoliosis, and hip-joint subluxation. She died at the age of 5 years. Whole-exome sequencing identified two homozygous variants c.133C>T; p.(Arg45Trp) and c.215dupA; p.(Tyr72Ter), respectively, in the two families, affecting an evolutionary conserved gene TMEM251 (NM_001098621.1). Immunofluorescence and confocal studies using human osteosarcoma cells indicated that TMEM251 is localized to the Golgi complex. However, p.Arg45Trp mutant TMEM251 protein was targeted less efficiently and the localization was punctate. Tmem251 knockdown by small interfering RNA induced dedifferentiation of rat

GCAF(TMEM251) regulates lysosome biogenesis by activating the mannose-6-phosphate pathway

“…Using its endogenous antibody, we observed that both long and short isoforms of TMEM251 colocalized with the cis-Golgi marker GM130 (Supplementary Fig. 4a, b ), which is consistent with the previous report that TMEM251-GFP is localized to Golgi 10 . A small fraction of TMEM251 also colocalized with the early endosome marker EEA1 and the lysosome marker LAMP2 (Supplementary Fig.…”

“…Mechanistically, GCAF is essential for the processing and activity of GNPT. Symptomatically, individuals who carried the pathogenic GCAF mutation displayed severe symptoms reminiscent of MLII 10 . Therefore, we propose classifying this MLII-like inherited metabolic disorder as Mucolipidosis type V.…”

“…In contrast, MLIII patients show a later onset of similar clinical symptoms. In early 2021, a new type of LSD similar to MLII was reported 10 . However, this disease is caused by mutations in TMEM251, a gene of unknown function, indicating that our knowledge of M6P biogenesis is incomplete.…”

A deeper insight into the deepest vertebrate of the sea

“…Furthermore, our estimated divergence times support the notion that hadal snail sh do have the ability to cross trenches, which is also consistent with recent studies on similarities in the composition of gut microbial taxa of two hadal snail sh species from the Kermadec and Mariana Trenches 51 . As a complement, the speci c loss of genes in hadal snail sh also suggests a possible ability to tolerate short-term starvation and achieve neutral buoyancy through lower skeletal density, all of which may further contribute to their ability to cross trenches 1,29,37,40,41 . In addition, a previous study suggested that hadal snail sh may develop in shallow waters during juvenile life and then descend to greater depths in adulthood 52 .…”

“…17). These two genes encode transmembrane proteins, and loss-of-function mutations have now been found that may affect bone mineral deposition and thus bone development and body growth 40,41 . Furthermore, many genes that determine chondrocyte differentiation and bone mineralization were found to be differentially expressed in the bones of hadal snail sh and Tanaka's snail sh.…”