Connexion

GENATLAS PHENOTYPE

last update : 24-02-2016

Symbol	PDB3
Location	5q35.3
HGNC id	16032
Name	Paget bone disease 3
Corresponding gene	SQSTM1
Main clinical features	bone pain, deformities, pathological fracture, an increased incidence of osteosarcomas and abnormal large, multinucleated osteoclasts with paramyxovirus-like nuclear inclusions chronic bone disease characterized by focal regions of increased bone resorption accompanied by increased formation of new, highly disorganized bone
Genetic determination	autosomal dominant
Prevalence	up to 30 p100 of Paget disease
Function/system disorder	osteo-articular
Type	disease

Gene product

Name

sequestosome 1

Mechanism(s)

Gene mutation	Effect	Comments

missense	abnormal protein/loss of function	disrupting the ubiquitin-binding function, which could result in abnormal activation of the NF-kappaB pathway and the subsequent activation of the osteoclasts
missense		mostly frequent P392L, affecting the ubiquitin-associated (UBA) domain

Remark(s)

. causing mutations identified, all of which cluster in and around the C-terminal ubiquitin-associated (UBA) domain; most common mutation identified thus far results in heterozygous substitution of a proline residue at codon 392 with a leucine (P392L), and is found in around one-quarter of PDB3 cases examined (PMID: 20971078))

mutated SQSTM1 accumulates in aggregates as the misfolded target of selective degradation as well as being a facilitator of the degradation process itself (PMID: 20971078))