LRP4 Mutations Alter Wnt/β-Catenin Signaling and Cause Limb and Kidney Malformations in Cenani-Lenz Syndrome

Li, Yun; Pawlik, Barbara; Elçioğlu, Nursel; Aglan, Mona; Kayserili, Hülya; Yiğit, Gökhan; Perçin, Ferda; Goodman, Frances R.; Nürnberg, Gudrun; Cenani, Asım; Urquhart, Jill; Chung, Boi Dinh; Ismail, Samira; Amr, Khalda; Aslanger, Ayça Dilruba; Becker, Christian; Netzer, Christian; Scambler, Peter J.; Eyaid, Wafaa; Hamamy, Hanan; Clayton‐Smith, Jill; Hennekam, Raoul C. M.; Nürnberg, Peter; Herz, Joachim; Temtamy, Samia; Wollnik, Bernd

doi:10.1016/j.ajhg.2010.03.004

Cited by 152 publications

(176 citation statements)

References 29 publications

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“…Upon closer inspection, Lrp4 flox/flox ;P Bi-2 -cre animals exhibited polysyndactyly (Fig. 1D), in line with documented abnormal distal limb development (25) resembling human CenaniLenz Syndrome (23). These phenotypes provide functional validity of the Lrp4 flox/flox line in creating an Lrp4-null mutation after Cre-mediated homologous recombination.…”

Section: Lrp4 Deletion In Osteoblasts/osteocytes Results In Increasedmentioning

confidence: 70%

Disruption of Lrp4 function by genetic deletion or pharmacological blockade increases bone mass and serum sclerostin levels

Chang

Krämer

Huber

et al. 2014

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

108

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We identified previously in vitro LRP4 (low-density lipoprotein receptor-related protein 4) as a facilitator of the WNT (Winglesstype) antagonist sclerostin and found mutations disrupting this function to be associated with high bone mass in humans similar to patients lacking sclerostin. To further delineate the role of LRP4 in bone in vivo, we generated mice lacking Lrp4 in osteoblasts/osteocytes or osteocytes only. Lrp4 deficiency promoted progressive cancellous and cortical bone gain in both mutants, although more pronouncedly in mice deficient in osteoblast/osteocyte Lrp4, consistent with our observation in human bone that LRP4 is most strongly expressed by osteoblasts and early osteocytes. Bone gain was related primarily to increased bone formation. Interestingly, Lrp4 deficiency in bone dramatically elevated serum sclerostin levels whereas bone expression of Sost encoding for sclerostin was unaltered, indicating that osteoblastic Lrp4 retains sclerostin within bone. Moreover, we generated anti-LRP4 antibodies selectively blocking sclerostin facilitator function while leaving unperturbed LRP4-agrin interaction, which is essential for neuromuscular junction function. These antibodies increased bone formation and thus cancellous and cortical bone mass in skeletally mature rodents. Together, we demonstrate a pivotal role of LRP4 in bone homeostasis by retaining and facilitating sclerostin action locally and provide a novel avenue to bone anabolic therapy by antagonizing LRP4 sclerostin facilitator function.LRP4 | SOST | sclerostin | WNT | bone anabolism

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Section: Lrp4 Deletion In Osteoblasts/osteocytes Results In Increasedmentioning

confidence: 70%

Disruption of Lrp4 function by genetic deletion or pharmacological blockade increases bone mass and serum sclerostin levels

Chang

Krämer

Huber

et al. 2014

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

108

View full text Add to dashboard Cite

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“…Additionally, there is rare involvement of craniofacial and nephrological features. 53,42 Harpf et al 24 suggested that there exist two grossly different clinical features in Cenani-Lenz type: (a) spoon-head type, and (b) oligodactyly type (Table 2). They also differentiated between consistent and inconsistent feature for CLS.…”

Section: Syndactyly Type I-d (Castilla Type; 4/5 Toes Syndactyly)mentioning

confidence: 99%

“…They also differentiated between consistent and inconsistent feature for CLS. Recently, Li et al 42 have shown that CLS, both spoon-head and oligodactyly types, and with or without kidney malformations are caused by mutations in LRP4 (chromosome 11p11.2), which is involved in Wnt/b-Catenin signaling. Interestingly, another molecular study showed that Cenani-Lenz phenotype with renal defects and hearing loss, and an autosomal dominant CenaniLenz-like non-syndromic oligodactyly are caused by genomic rearrangements of GREM1-FMN1 locus on chromosome 15q13.3.…”

Section: Syndactyly Type I-d (Castilla Type; 4/5 Toes Syndactyly)mentioning

confidence: 99%

Syndactyly: phenotypes, genetics and current classification

2012

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Syndactyly is one of the most common hereditary limb malformations depicting the fusion of certain fingers and/or toes. It may occur as an isolated entity or a component of more than 300 syndromic anomalies. Syndactylies exhibit great inter-and intra-familial clinical variability. Even within a subject, phenotype can be unilateral or bilateral and symmetrical or asymmetrical. At least nine non-syndromic syndactylies with additional sub-types have been characterized. Most of the syndactyly types are inherited as autosomal dominant but two autosomal recessive and an X-linked recessive entity have also been described. Whereas the underlying genes/mutations for types II-1, III, IV, V, and VII have been worked out, the etiology and molecular basis of the other syndactyly types remain unknown. In this communication, based on an overview of wellcharacterized isolated syndactylies, their cardinal phenotypes, inheritance patterns, and clinical and genetic heterogeneities, a 'current classification scheme' is presented. Despite considerable progress in the understanding of syndactyly at clinical and molecular levels, fundamental questions regarding the disturbed developmental mechanisms leading to fused digits, remain to be answered.

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“…Not only secreted Wise is able to inhibit Wnt signaling, but endoplasmic reticulum (ER)-retained Wise is also able to do so by reducing cell surface LRP6 (Guidato and Itasaki 2007). Wise also binds the LRP4 receptor (Ohazama et al 2008), which is able to modulate Wnt signaling mediated by LRP5 and -6 (Ohazama et al 2008;Li et al 2010).…”

Section: Wise and Sostmentioning

confidence: 99%