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Various types of LRP5 mutations in four patients with osteoporosis‐pseudoglioma syndrome: Identification of a 7.2‐kb microdeletion using oligonucleotide tiling microarray
Author(s) -
Narumi Satoshi,
Numakura Chikahiko,
Shiihara Takashi,
Seiwa Chizuru,
Nozaki Yasuyuki,
Yamagata Takanori,
Momoi Mariko Y.,
Watanabe Yoriko,
Yoshino Makoto,
Matsuishi Toyojiro,
Nishi Eriko,
Kawame Hiroshi,
Akahane Tsutomu,
Nishimura Gen,
Emi Mitsuru,
Hasegawa Tomonobu
Publication year - 2010
Publication title -
american journal of medical genetics part a
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.064
H-Index - 112
eISSN - 1552-4833
pISSN - 1552-4825
DOI - 10.1002/ajmg.a.33177
Subject(s) - genetics , lrp5 , biology , exon , mutation , nonsense mutation , missense mutation , microbiology and biotechnology , gene , wnt signaling pathway
Osteoporosis‐pseudoglioma syndrome (OPS; OMIM 259770) is an autosomal‐recessive genetic disorder characterized by severe osteoporosis and visual disturbance from childhood. Biallelic mutations in the low‐density lipoprotein receptor‐related protein 5 gene ( LRP5 ) have been frequently detected, while a subset of patients had only one or no detectable mutation. We report on the clinical and molecular findings of four unrelated Japanese patients with the syndrome. The four patients had typical skeletal and ocular phenotypes of OPS, namely severe juvenile osteoporosis and early‐onset visual disturbance, with or without mental retardation. We undertook standard PCR‐based sequencing for LRP5 and found four missense mutations (p.L145F, p.T244M, p.P382L, and p.T552M), one nonsense mutation (p.R1534X), and one splice site mutation (c.1584+1G>A) among four OPS patients. Although three patients had two heterozygous mutations, one had only one heterozygous splice site mutation. In this patient, RT‐PCR from lymphocytic RNA demonstrated splice error resulting in 63‐bp insertion between exons 7 and 8. Furthermore, the patient was found to have only mutated RT‐PCR fragment, implying that a seemingly normal allele did not express LRP5 mRNA. We then conducted custom‐ designed oligonucleotide tiling microarray analyses targeted to a 600‐kb genome region harboring LRP5 and discovered a 7.2‐kb microdeletion encompassing exons 22 and 23 of LRP5 . We found various types of LRP5 mutations, including an exon‐level deletion that is undetectable by standard PCR‐based mutation screening. Oligonucleotide tiling microarray seems to be a powerful tool in identifying cryptic structural mutations. © 2009 Wiley‐Liss, Inc.