An Autosomal Dominant High Bone Mass Phenotype in Association With Craniosynostosis in an Extended Family Is Caused by an LRP5 Missense Mutation

Abstract

Gain-of-function mutations in LRP5 have been shown to cause high BMD disorders showing variable expression of some clinical symptoms, including torus palatinus and neurological complications. In an extended family, we were able to add craniosynostosis and developmental delay to the clinical spectrum associated with LRP5 mutations.We report on an extended four-generation family with 13 affected individuals (7 men and 6 women) in which an autosomal dominant type of osteosclerosis segregates. Osteosclerosis was most pronounced in the cranial base and calvarium, starting in early childhood with variable expression and a progressive character. Craniosynostosis at an early age was reported in four affected family members (two males and two females). The patients also presented with dysmorphic features (macrocephaly, brachycephaly, wide and high forehead, hypertelorism, prominent cheekbones, prominent jaw). They have normal height and proportions. Neurological complications like entrapment of cranial nerves resulting in optical nerve atrophy, hearing loss, and facial palsy were reported in two individuals. A mild developmental delay was reported in three affected individuals. None of the patients have torus palatinus, increased rate of fractures, osteomyelitis, hepatosplenomegaly, or pancytopenia. A missense mutation 640G→A (A214T) in the low-density lipoprotein receptorrelated protein 5 (LRP5) gene was found in all affected individuals analyzed, including cases in whom craniosynostosis, a mild developmental delay, and/or macrocephaly is observed. To our knowledge, this is the first report in the literature of patients presenting with autosomal dominant osteosclerosis in whom a variable expression of craniosynostosis, macrocephaly, and mild developmental delay is observed, which is most likely associated with a mutation in the LRP5 gene. These phenotypes can therefore be added to the clinical spectrum of LRP5-associated bone disorders.

Structure-based mutation analysis shows the importance of LRP5 β-propeller 1 in modulating Dkk1-mediated inhibition of Wnt signaling

“…This indicates that among the four β-propellers, β-propeller 1 plays an important role in mediating resistance to Dkk1 function in vitro and in turn suggests that LRP5 β-propeller 1 variants in addition to G171V could result in the high bone mass phenotype in vivo (Johnson and Summerfield, 2005). This hypothesis is supported by recent reports indicating that several LRP5 β-propeller 1 mutations (D111Y, G171R, A214T, A214V, A242T and T243I) have been identified from patients with increased bone density, and that these LRP5 variants activate Wnt signaling by relieving Dkk1-mediated inhibition in an in vitro TCF signaling assay (Van Wesenbeeck et al, 2003;Ai et al, 2005b;Koay and Brown, 2005;Kwee et al, 2005). While a majority of our in vitro studies with G171V equivalent mutations in β-propeller 1 showed inhibition of Dkk1 function, interestingly two of them (A214V and M282V) have been identified in humans with increased bone density (Balemans et al, 2006).…”

Canonical Wnt signalling activates TAZ through PP1A during osteogenic differentiation

“…A gain of function mutation in the Wnt receptor LRP5 leads to high bone mass in humans. [20][21][22] Genetic deletion of LRP5 causes a decrease in bone mass in mice.…”

“…A gain of function mutation in the Wnt receptor LRP5 leads to high bone mass in humans. [20][21][22] Genetic deletion of LRP5 causes a decrease in bone mass in mice. 23 Transgenic mice expressing Wnt10b under the control of an osteoblast-specific promoter show increased bone mass.…”

Genetic Causes of Craniosynostosis: An Update

“…These are classical pathways that are involved in early embryonic development. But also, many of the gene defects may act through causing perturbations in osteogenesis, such as filaminopathies, hypophosphatasia [Currarino, 2007;Murthy, 2009], mucopolysaccharidoses [Ziyadeh et al, 2013], osteosclerosis [Kato et al, 2002;Kwee et al, 2005;Simpson et al, 2007Simpson et al, , 2009, and pycnodysostosis [Osimani et al, 2010;Bertola et al, 2011;Berenguer et al, 2012;Caracas et al, 2012;Twigg and Wilkie, 2015]. These diagnoses include potentially treatable conditions, for which early recognition is particularly important [Wilkie et al, 2017], and more and more mutations are being identified in genes that are involved in brain development or that are associated with intellectual disability and/or behavioral anomalies (such as ASXL1 , ANKDR11 , KAT6A , KMT2D , and ZEB2 ) [Twigg and Wilkie, 2015].…”