Premium
A mutation in the signal sequence of LRP5 in a family with an osteoporosis‐pseudoglioma syndrome (OPPG)‐like phenotype indicates a novel disease mechanism for trinucleotide repeats
Author(s) -
Chung BoiDinh,
Kayserili Hülya,
Ai Minrong,
Freudenberg Jan,
Üzümcü Abdullah,
Uyguner Oya,
Bartels Cynthia F.,
Höning Stefan,
Ramirez Alfredo,
Hanisch FranzGeorg,
Nürnberg Gudrun,
Nürnberg Peter,
Warman Matthew L.,
Wollnik Bernd,
Kubisch Christian,
Netzer Christian
Publication year - 2009
Publication title -
human mutation
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.981
H-Index - 162
eISSN - 1098-1004
pISSN - 1059-7794
DOI - 10.1002/humu.20916
Subject(s) - biology , genetics , phenotype , mutation , mechanism (biology) , trinucleotide repeat expansion , sequence (biology) , lrp5 , gene , wnt signaling pathway , allele , philosophy , epistemology
We extend the spectrum of phenotypes caused by mutations in the Wnt/Norrin coreceptor low‐density lipoprotein receptor‐related protein 5 (LRP5) by identifying two novel types of mutation in related individuals whose presenting features were profound muscle hypotonia, mild mental retardation, blindness, and growth retardation. One mutation removes 6 out of 9 consecutive leucine residues in the LRP5 signal peptide (c.43_60del or p.Leu15_Leu20del), which impairs polypeptide entry into the endoplasmic reticulum (ER), trafficking to the cell membrane, and signal transduction. The second mutation resulted from nonhomologous recombination between Alu repeat sequences, which deleted exons 14–16 and would produce a nonfunctional, truncated, and frameshifted polypeptide, if expressed [chr11:g.(13871447_1387511)_(13879636_13879700)del (NW_925106.1) or p.Pro1010GlnfsX38]. We confirmed that the length of the LRP5 signal peptide poly‐leucine repeat is polymorphic in the general population, and, importantly, we were able to demonstrate in independent in vitro assays that different allele sizes affect receptor processing and signal transduction. Consequently, this polymorphism may have physiologic effects in vivo. This latter finding is relevant since through a genomewide search we identified nearly 400 human proteins that contain poly‐leucine repeats within their signal peptide. We chose 18 of these proteins and genotyped the underlying trinucleotide repeat in healthy Caucasian individuals. More than one length allele was observed in one‐half of the proteins. We therefore propose that natural variation in poly‐leucine‐stretches within signal peptides constitutes a currently unrecognized source of variability in protein translation and expression. Hum Mutat 0, 1–8, 2009. © 2009 Wiley‐Liss, Inc.