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Clinical and molecular findings in osteoporosis-pseudoglioma syndrome.
Am J Hum Genet. 2005 Nov; 77(5):741-53.AJ

Abstract

Mutations in the low-density lipoprotein receptor-related protein 5 gene (LRP5) cause autosomal recessive osteoporosis-pseudoglioma syndrome (OPPG). We sequenced the coding exons of LRP5 in 37 probands suspected of having OPPG on the basis of the co-occurrence of severe congenital or childhood-onset visual impairment with bone fragility or osteoporosis recognized by young adulthood. We found two putative mutant alleles in 26 probands, only one mutant allele in 4 probands, and no mutant alleles in 7 probands. Looking for digenic inheritance, we sequenced the genes encoding the functionally related receptor LRP6, an LRP5 coreceptor FZD4, and an LRP5 ligand, NDP, in the four probands with one mutant allele, and, looking for locus heterogeneity, we sequenced FZD4 and NDP in the seven probands with no mutations, but we found no additional mutations. When we compared clinical features between probands with and without LRP5 mutations, we found no difference in the severity of skeletal disease, prevalence of cognitive impairment, or family history of consanguinity. However, four of the seven probands without detectable mutations had eye pathology that differed from pathology previously described for OPPG. Since many LRP5 mutations are missense changes, to differentiate between a disease-causing mutation and a benign variant, we measured the ability of wild-type and mutant LRP5 to transduce Wnt and Norrin signal ex vivo. Each of the seven OPPG mutations tested, had reduced signal transduction compared with wild-type mutations. These results indicate that early bilateral vitreoretinal eye pathology coupled with skeletal fragility is a strong predictor of LRP5 mutation and that mutations in LRP5 cause OPPG by impairing Wnt and Norrin signal transduction.

Authors+Show Affiliations

Department of Genetics and Center for Human Genetics, Case School of Medicine and University Hospitals of Cleveland, Cleveland, OH, 44106, USA.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

16252235

Citation

Ai, Minrong, et al. "Clinical and Molecular Findings in Osteoporosis-pseudoglioma Syndrome." American Journal of Human Genetics, vol. 77, no. 5, 2005, pp. 741-53.
Ai M, Heeger S, Bartels CF, et al. Clinical and molecular findings in osteoporosis-pseudoglioma syndrome. Am J Hum Genet. 2005;77(5):741-53.
Ai, M., Heeger, S., Bartels, C. F., & Schelling, D. K. (2005). Clinical and molecular findings in osteoporosis-pseudoglioma syndrome. American Journal of Human Genetics, 77(5), 741-53.
Ai M, et al. Clinical and Molecular Findings in Osteoporosis-pseudoglioma Syndrome. Am J Hum Genet. 2005;77(5):741-53. PubMed PMID: 16252235.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Clinical and molecular findings in osteoporosis-pseudoglioma syndrome. AU - Ai,Minrong, AU - Heeger,Shauna, AU - Bartels,Cynthia F, AU - Schelling,Deborah K, AU - ,, Y1 - 2005/09/27/ PY - 2005/06/20/received PY - 2005/08/10/accepted PY - 2005/10/28/pubmed PY - 2006/3/15/medline PY - 2005/10/28/entrez SP - 741 EP - 53 JF - American journal of human genetics JO - Am. J. Hum. Genet. VL - 77 IS - 5 N2 - Mutations in the low-density lipoprotein receptor-related protein 5 gene (LRP5) cause autosomal recessive osteoporosis-pseudoglioma syndrome (OPPG). We sequenced the coding exons of LRP5 in 37 probands suspected of having OPPG on the basis of the co-occurrence of severe congenital or childhood-onset visual impairment with bone fragility or osteoporosis recognized by young adulthood. We found two putative mutant alleles in 26 probands, only one mutant allele in 4 probands, and no mutant alleles in 7 probands. Looking for digenic inheritance, we sequenced the genes encoding the functionally related receptor LRP6, an LRP5 coreceptor FZD4, and an LRP5 ligand, NDP, in the four probands with one mutant allele, and, looking for locus heterogeneity, we sequenced FZD4 and NDP in the seven probands with no mutations, but we found no additional mutations. When we compared clinical features between probands with and without LRP5 mutations, we found no difference in the severity of skeletal disease, prevalence of cognitive impairment, or family history of consanguinity. However, four of the seven probands without detectable mutations had eye pathology that differed from pathology previously described for OPPG. Since many LRP5 mutations are missense changes, to differentiate between a disease-causing mutation and a benign variant, we measured the ability of wild-type and mutant LRP5 to transduce Wnt and Norrin signal ex vivo. Each of the seven OPPG mutations tested, had reduced signal transduction compared with wild-type mutations. These results indicate that early bilateral vitreoretinal eye pathology coupled with skeletal fragility is a strong predictor of LRP5 mutation and that mutations in LRP5 cause OPPG by impairing Wnt and Norrin signal transduction. SN - 0002-9297 UR - https://www.unboundmedicine.com/medline/citation/16252235/Clinical_and_molecular_findings_in_osteoporosis_pseudoglioma_syndrome_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0002-9297(07)63357-6 DB - PRIME DP - Unbound Medicine ER -