Abstract
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.Wereport on the clinical and molecular findings of four unrelated Japanese patientswiththe syndrome.Thefour 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.
| Original language | English |
|---|---|
| Pages (from-to) | 133-140 |
| Number of pages | 8 |
| Journal | American Journal of Medical Genetics, Part A |
| Volume | 152 |
| Issue number | 1 |
| DOIs | |
| Publication status | Published - 2010 Jan |
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Keywords
- Comparative genomic hybridization
- Low-density lipoprotein receptor-related protein 5 (LRP5)
- Microdeletion
- Mutation
- Osteoporosis-pseudoglioma syndrome
ASJC Scopus subject areas
- Genetics(clinical)
- Genetics
Cite this
Various types of LRP5 mutations in four patients with osteoporosis- pseudoglioma syndrome : Identification of a 7.2-kb microdeletion using oligonucleotide tiling microarray. / 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.
In: American Journal of Medical Genetics, Part A, Vol. 152, No. 1, 01.2010, p. 133-140.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Various types of LRP5 mutations in four patients with osteoporosis- pseudoglioma syndrome
T2 - Identification of a 7.2-kb microdeletion using oligonucleotide tiling microarray
AU - Narumi, Satoshi
AU - Numakura, Chikahiko
AU - Shiihara, Takashi
AU - Seiwa, Chizuru
AU - Nozaki, Yasuyuki
AU - Yamagata, Takanori
AU - Momoi, Mariko Y.
AU - Watanabe, Yoriko
AU - Yoshino, Makoto
AU - Matsuishi, Toyojiro
AU - Nishi, Eriko
AU - Kawame, Hiroshi
AU - Akahane, Tsutomu
AU - Nishimura, Gen
AU - Emi, Mitsuru
AU - Hasegawa, Tomonobu
PY - 2010/1
Y1 - 2010/1
N2 - 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.Wereport on the clinical and molecular findings of four unrelated Japanese patientswiththe syndrome.Thefour 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.
AB - 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.Wereport on the clinical and molecular findings of four unrelated Japanese patientswiththe syndrome.Thefour 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.
KW - Comparative genomic hybridization
KW - Low-density lipoprotein receptor-related protein 5 (LRP5)
KW - Microdeletion
KW - Mutation
KW - Osteoporosis-pseudoglioma syndrome
UR - http://www.scopus.com/inward/record.url?scp=75149112678&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=75149112678&partnerID=8YFLogxK
U2 - 10.1002/ajmg.a.33177
DO - 10.1002/ajmg.a.33177
M3 - Article
C2 - 20034086
AN - SCOPUS:75149112678
VL - 152
SP - 133
EP - 140
JO - American Journal of Medical Genetics
JF - American Journal of Medical Genetics
SN - 1552-4868
IS - 1
ER -