Truncating mutations in <i>LRP4</i> lead to a prenatal lethal form of Cenani–Lenz syndrome

Lindy, Amanda; Bupp, Caleb; McGee, Stephen J.; Steed, Erin H.; Stevenson, Roger E.; Basehore, Monica J.; Friez, Michael J.

doi:10.1002/ajmg.a.36647

Cited by 25 publications

(25 citation statements)

References 19 publications

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“…S1 and S2), suggesting that Lrp4 loss in other cell types (e.g., chondrocytes) may contribute to this deficit. Interestingly, the digit deficit resembles the hand defect for sclerosteosis patients as well as for patients with CenaniLenz syndrome (27)(28)(29). Lrp4 mutations are also identified in patients with Cenani-Lenz syndrome, in addition to bone-related diseases (27)(28)(29).…”

Section: Discussionmentioning

confidence: 98%

Lrp4 in osteoblasts suppresses bone formation and promotes osteoclastogenesis and bone resorption

Xiong

Jung

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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Bone mass is maintained by balanced activity of osteoblasts and osteoclasts. Lrp4 (low-density lipoprotein receptor related protein 4) is a member of the LDL receptor family, whose mutations have been identified in patients with high-bone-mass disorders, such as sclerosteosis and van Buchem diseases. However, it remains unknown whether and how Lrp4 regulates bone-mass homeostasis in vivo. Here we provide evidence that Lrp4-null mutation or specific mutation in osteoblast-lineage cells increased cortical and trabecular bone mass, which was associated with elevated bone formation and impaired bone resorption. This phenotype was not observed in osteoclast-selective Lrp4 knockout mice. Mechanistic studies indicate that loss of Lrp4 function in osteoblast-lineage cells increased serum levels of sclerostin, a key factor for bone-mass homeostasis that interacts with Lrp4, but abolished the inhibition of Wnt/β-catenin signaling and osteoblastic differentiation by sclerostin. Concomitantly, sclerostin induction of RANKL (receptor activator of nuclear kappa B ligand) was impaired, leading to a lower ratio of RANKL over OPG (osteoprotegerin) (a key factor for osteoclastogenesis). Taken together, these results support the view for Lrp4 as a receptor of sclerostin to inhibit Wnt/β-catenin signaling and bone formation and identify Lrp4 as a critical player in bonemass homeostasis.one remodeling is a dynamic process essential for maintenance of skeletal integrity and bone homeostasis (1). Bone mass is tightly regulated by bone-forming osteoblasts (OBs) and bone-resorbing osteoclasts (OCs). OBs are differentiated from bone marrow stromal cells (BMSCs) or mesenchymal progenitor cells, whereas OCs are derived from hematopoietic bone marrow macrophages or myeloid monocytes (BMMs). The balance of bone formation and resorption is critical for maintenance of healthy bone mass. The imbalance of bone formation and resorption could result in high-bone-mass disorders such as sclerosteosis and van Buchem disease or bone loss such as osteoporosis.The canonical Wnt/β-catenin signaling is critical to regulate bone-mass homeostasis (1, 2). Binding of Wnt ligands to a dualreceptor complex of frizzled and Lrp5/6 leads to accumulation of cytoplasmic β-catenin and translocation of β-catenin into the nucleus to regulate gene expression. This pathway is required for commitment of mesenchymal stem cells to the OB lineage, OB precursor cell proliferation and differentiation, and OC genesis and activation (1-3). Clinically, Lrp5 mutations are associated with the osteoporosis-pseudoglioma syndrome, a low-bone-mass disorder (4), as well as with high-bone-mass disorders (5, 6).Lrp4 is a member of LDL family protein, containing a large extracellular region with multiple LDLa, EGF-like, and β-propeller repeats, a transmembrane domain, and a short C-terminal region. Lrp4 is a receptor of agrin (7,8), critical for neuromuscular junction formation. Mice lacking Lrp4 (null allele) die at birth because of inability to breathe (9). Lrp4 is also highly related to...

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Section: Discussionmentioning

confidence: 98%

Lrp4 in osteoblasts suppresses bone formation and promotes osteoclastogenesis and bone resorption

Xiong

Jung

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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“…The membrane scarcity of LRP4 has been demonstrated to downregulate Wnt signaling via an unknown mechanism. Recently, two homozygous truncating mutations in that gene have been shown to underlay a prenatally lethal form of the syndrome …”

Section: Introductionmentioning

confidence: 99%

A Novel Domain-Specific Mutation in a Sclerosteosis Patient Suggests a Role of LRP4 as an Anchor for Sclerostin in Human Bone

Fijałkowski

Geets

Steenackers

et al. 2016

Journal of Bone and Mineral Research

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Mutations in the LRP4 gene, coding for a Wnt signaling coreceptor, have been found to cause several allelic conditions. Among these, two are characterized by a strong skeletal involvement, namely sclerosteosis and Cenani-Lenz syndrome. In this work, we evaluated the role of LRP4 in the pathophysiology of these diseases. First, we report a novel LRP4 mutation, leading to the substitution of arginine at position 1170 in glutamine, identified in a patient with sclerosteosis. This mutation is located in the central cavity of the third b-propeller domain, which is in line with two other sclerosteosis mutations we previously described. Reporter assays demonstrate that this mutation leads to impaired sclerostin inhibition of Wnt signaling. Moreover, we compared the effect of this novel variant to mutations causing Cenani-Lenz syndrome and show that impaired membrane trafficking of the LRP4 protein is the likely mechanism underlying Cenani-Lenz syndrome. This is in contrast to sclerosteosis mutations, previously shown to impair the binding between LRP4 and sclerostin. In addition, to better understand the biology of LRP4, we investigated the circulating sclerostin levels in the serum of a patient suffering from sclerosteosis owing to a LRP4 mutation. We demonstrate that impaired sclerostin binding to the mutated LRP4 protein leads to dramatic increase in circulating sclerostin in this patient. With this study, we provide the first evidence suggesting that LRP4 is responsible for the retention of sclerostin in the bone environment in humans. These findings raise potential concerns about the utility of determining circulating sclerostin levels as a marker for other bone-related parameters. Although more studies are needed to fully understand the mechanism whereby LRP4 facilitates sclerostin action, it is clear that this protein represents a potent target for future osteoporosis therapies and an interesting alternative for the antisclerostin treatment currently under study.

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“…Sequences were processed using NextGENe software (SoftGenetics, LLC, State College, PA) and .vcf files were uploaded to BENCH lab NGS (Cartagenia, Leuven, Belgium) for filtering and subsequent analysis of variants of interest as previously described [Lindy et al, 2014]. Benign variants were separated using the dbSNP, 1000 Genomes, and ESP6500 databases with an allele frequency cut off of 0.033.…”

Section: Methodsmentioning

confidence: 99%

Novel pathogenic variants in FOXP3 in fetuses with echogenic bowel and skin desquamation identified by ultrasound

Louie

Tan

Gilner

et al. 2017

American J of Med Genetics Pt A

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Immunodysregulation, Polyendocrinopathy, Enteropathy, X-linked (IPEX) syndrome is a rare, X-linked recessive disease that affects regulatory T cells (Tregs) resulting in diarrhea, enteropathy, eczema, and insulin-dependent diabetes mellitus. IPEX syndrome is caused by pathogenic alterations in FOXP3 located at Xp11.23. FOXP3 encodes a transcription factor that interacts with several partners, including NFAT and NF-κB, and is necessary for the proper cellular differentiation of Tregs. Although variable, the vast majority of IPEX syndrome patients have onset of disease during infancy with severe enteropathy. Only five families with prenatal presentation of IPEX syndrome have been reported. Here, we present two additional prenatal onset cases with novel inherited frameshift pathogenic variants in FOXP3 that generate premature stop codons. Ultrasound findings in the first patient identified echogenic bowel, echogenic debris, scalp edema, and hydrops. In the second patient, ultrasound findings included polyhydramnios with echogenic debris, prominent fluid-filled loops of bowel, and echogenic bowel. These cases further broaden the phenotypic spectrum of IPEX syndrome by describing previously unappreciated prenatal ultrasound findings associated with the disease.

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Truncating mutations in LRP4 lead to a prenatal lethal form of Cenani–Lenz syndrome

Cited by 25 publications

References 19 publications

Lrp4 in osteoblasts suppresses bone formation and promotes osteoclastogenesis and bone resorption

Lrp4 in osteoblasts suppresses bone formation and promotes osteoclastogenesis and bone resorption

A Novel Domain-Specific Mutation in a Sclerosteosis Patient Suggests a Role of LRP4 as an Anchor for Sclerostin in Human Bone

Novel pathogenic variants in FOXP3 in fetuses with echogenic bowel and skin desquamation identified by ultrasound

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