Clinical And Molecular Findings In Osteoporosis-Pseudoglioma Syndrome

Authors:
Minrong Ai, Shauna Heeger, Cynthia F. Bartels, Deborah K. Schelling, and the Osteoporosis-Pseudoglioma Collaborative Group (1)

Author Affiliations:
Department of Genetics and Center for Human Genetics, Case School of Medicine and University Hospitals of Cleveland, Cleveland

Mutations in the low-density lipoprotein receptor related protein 5 gene (LRP5) cause autosomal recessive osteoporosis-pseudoglioma syndrome (OPPG). The authors 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.

Looking for digenic inheritance, they 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, they sequenced FZD4 and NDP in the seven probands with no mutations, but found no additional mutations.

Comparisons were made of the clinical features between probands with and without LRP5 mutations. They also measured the ability of wild-type and mutant LRP5 to transduce Wnt and Norrin signal ex vivo.

The 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.

(1) The Osteoporosis-Pseudoglioma Collaborative Group includes clinicians who have cared for the patients with OPPG. The clinicians who ascertained, synthesized, and provided previously unpublished data specifically for this study are included as coauthors. Their names and affiliations are listed in the Acknowledgments.

Abstract available online.

(C) American Journal of Human Genetics.

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