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.

Obesity has become a major health problem worldwide. To date, more than 25 different syndromic forms of obesity are known in which one (monogenic) or multiple (polygenic) genes are involved. This review gives an overview of these forms and focuses more in detail on 6 syndromes: Prader Willi Syndrome and Prader Willi like phenotype, Bardet Biedl Syndrome, Alström Syndrome, Wilms tumor, Aniridia, Genitourinary malformations and mental Retardation syndrome and 16p11.2 (micro)deletions. Years of research provided plenty of information on the molecular genetics of these disorders and the obesity phenotype leading to a more individualized treatment of the symptoms, however, many questions still remain unanswered. As these obesity syndromes have different signs and symptoms in common, it makes it difficult to accurately diagnose patients which may result in inappropriate treatment of the disease. Therefore, the big challenge for clinicians and scientists is to more clearly differentiate all syndromic forms of obesity to provide conclusive genetic explanations and eventually deliver accurate genetic counseling and treatment. In addition, further delineation of the (functions of the) underlying genes with the use of array- or next-generation sequencing-based technology will be helpful to unravel the mechanisms of energy metabolism in the general population.

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Neuropeptide Y (NPY) and its G protein-coupled NPY Y2 Receptor (NPY2R) are highly expressed in orexigenic NPY/Agouti-related peptide neurons within the arcuate nucleus, a major integrator of appetite control in the hypothalamus. As NPY and NPY2R are interesting candidate genes for obesity, we hypothesized that a genetic variation in these genes might be implicated in the pathogenesis of obesity. In the first part of this study, we performed a mutation analysis of the coding region of NPY and NPY2R with high-resolution melting curve analysis. For the highly conserved NPY gene, an extended population of 436 obese children and adolescents was screened, while for NPY2R, a smaller subset of 306 patients was used. A control population of 300 healthy individuals was screened for NPY2R to determine the general prevalence of the variants found among patients. Direct sequencing was performed for samples with melting patterns deviating from wild-type. In the second part of this study, Multiplex Amplicon Quantification (MAQ) analysis was performed in 308 obese children and adolescents to detect copy number variation (CNV) in the NPY2R region. Mutation analysis of the NPY gene led to the identification of one common missense variant (L7P; MAF 0.04), while the screening of the NPY2R gene resulted in the identification of one rare missense variant F87I in the patient population. In our CNV analysis, we could not identify copy number variation in the NPY2R region among obese children and adolescents. In summary, this study clearly indicates that genetic variation in NPY and NPY2R is at low frequency and thus does not make a major contribution to the obese phenotype in the general population.

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