非表示:
キーワード:
-
要旨:
Mutations in ROR2 cause dominant brachydactyly type B (BDB1) or recessive Robinow syndrome (RRS),
each characterized by a distinct combination of phenotypic features. We here report a novel nonsense
mutation in ROR2 (c.1324C>T; p.R441X) causing intracellular protein truncation in a patient exhibiting features
of RRS in conjunction with severe recessive brachydactyly. The mutation is located at the same position
as a previously described frame shift mutation causing dominant BDB1. To investigate the apparent
discrepancy in phenotypic outcome, we analysed ROR2 protein stability and distribution in stably transfected
cell lines expressing exact copies of several human RRS and BDB1 intracellular mutations. RRS
mutant proteins were less abundant and retained intracellularly, although BDB1 mutants were stable and predominantly
located at the cell membrane. The p.R441X mutation showed an intermediate pattern with membrane
localization but also high endoplasmic reticulum retention. Furthermore, we observed a correlation
between the severity of BDB1, the location of the mutation, and the amount of membrane-associated
ROR2. Membrane protein fraction quantification revealed a gradient of distribution and stability correlating
with the clinical phenotypes. This gradual model was confirmed by crossing mouse models for RRS and
BDB1, yielding double heterozygous animals that exhibited an intermediate phenotype. We propose a
model in which the RRS versus the BDB1 phenotype is determined by the relative degree of protein retention/
degradation and the amount of mutant protein reaching the plasma membrane.
