Dataset Information

The intracellular localization and the ionic permeation of TRPV6 triggers chronic pancreatitis, skeletal dysplasia and is connected to mucolipidosis type II (data part II)

ABSTRACT: Heterozygous TRPV6 mutations, which reduce significantly the Ca2+-permeability of the channel, lead to chronic pancreatitis and, if both TRPV6-alleles are affected, to skeletal dysplasia with neonatal transient hyperparathyroidism (TNHP) of newborns. We show that TRPV6 channels are localized in intracellular vesicles in pancreatic acinar cells, in the syncytiotrophoblast layer of the placenta and, after overexpression, in HEK293 cells. We identify three motifs within the TRPV6 sequence a N-glycosylation site, an ER- and a sorting motif which in concerted action leads to an intracellular localisation. The transport to vesicles depends on the N-glycosylation site of TRPV6. We found that the channel interacts with the cation independent mannose-6-phosphate receptor (CI-M6PR/IGF2R) indicating that TRPV6 is a target of the GNPTAB enzyme which targets proteins for endosomes/lysosomes by generating a mannose-6-phosphate residue at the N-glykosyl site chain of TRPV6. Defects in the GNTPAB enzyme cause mucolipidosis type II and patients show at the time of birth overlapping defects with patients with TRPV6 mutations. We show that a TRPV6 mutation, I223T, frequently found in patients with pancreatitis/skeletal dysplasia sticks to the ER but shows not reduced channel activity. The I223T mutation causes the diseases because the TRPV6 channel is not transferred to intracellular vesicles.

INSTRUMENT(S):

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Cell Culture

SUBMITTER: Claudia Fecher-Trost

LAB HEAD: Ulrich Wissenbach

PROVIDER: PXD065789 | Pride | 2026-02-02

REPOSITORIES: Pride

ACCESS DATA

Dataset's files

Source:

			Action	DRS
	IP_GFP_NN_Cotraf_ALG160_1.mgf	Mgf
	IP_GFP_NN_Cotraf_ALG160_1.raw	Raw
	IP_GFP_NN_Cotraf_ALG160_2.mgf	Mgf
	IP_GFP_NN_Cotraf_ALG160_2.raw	Raw
	IP_GFP_NN_Cotraf_ALG160_3.mgf	Mgf

Items per page:

1 - 5 of 65

Publications

The intracellular localization and the ionic permeation of TRPV6 triggers chronic pancreatitis, skeletal dysplasia and is connected to mucolipidosis type II.

Fecher-Trost Claudia C Gehl Anna-Lena AL Trunk Alessa A Hellmich Johanna J Wesely Christine C Löhr Heidi H Buchholz Stefanie S Cole Marnie M Beck Andreas A Meyer Markus R MR Wissenbach Ulrich U

Cell communication and signaling : CCS 20251223 1

PMID: 41437274

Similar Datasets

Project description:<p><ol> <li>Several different genes cause, when mutated, increased urinary phosphate excretion and hypophosphatemia leading to rickets/osteomalacia; however, the majority of phosphate-wasting disorders has not yet been defined at the molecular level. Identification of phosphate-regulating genes has provided important novel insights into the mechanism contributing to phosphate homeostasis, which remains incompletely understood. We therefore pursue exome-wide nucleotide sequence analysis to define the underlying mutations, which is expected to provide novel insights into the regulation of this important mineral.</li> <li>Virtually nothing is known about the genetic mutations that cause non-syndromic structural abnormalities involving the urinary tract, which represent about 50% of the causes of end-stage renal disease (ESRD). The completion of the human genome project and the technological advances that allow low cost whole exome sequencing have now made it feasible to readily search for the cause of different inherited disorders in humans, particularly if clinical information and genomic DNA is available from larger kindreds with multiple affected members that can be used for mapping the disease-causing genetic locus. Furthermore, catalogs were generated that document the expression profiles of numerous genes during embryonic, fetal, and postnatal development, thereby supporting the exploration of kidney involvement in animal models of different diseases and in human genetic syndromes. We therefore plan to define the mechanisms leading to inherited disorders of the urogenital tract and the kidneys by establishing the causative genetic defects through a combination of genetic mapping and whole exome sequencing.</li> <li>Hajdu-Cheney Syndrome (HCS) is a rare autosomal-dominant skeletal disorder characterized by severe osteoporosis, acroosteolysis of the distal phalanges, renal cysts and other abnormalities. Our goal is to identify the genetic cause of HCS using exome sequencing.</li> <li>Opsismodysplasia is a very rare recessive spondylometaphyseal dysplasia characterized by delayed epiphyseal ossification, shortness of bones and sometimes low serum phosphate levels. Discovery of the causing mutation will give us insights into the pathogenesis of this often lethal disease.</li> </ol></p>