Kinoshita, A. et al. Domain-specific mutations in TGFB1 result in Camurati-Engelmann disease. Nat. Genet. 26, 19-20

Department of Orthopaedic Surgery, Akita University, Akita, Akita, Japan
Nature Genetics (Impact Factor: 29.35). 10/2000; 26(1):19-20. DOI: 10.1038/79128
Source: PubMed


Camurati-Engelmann disease (CED, MIM 131300) is an autosomal dominant, progressive diaphyseal dysplasia characterized by hyperosteosis and sclerosis of the diaphyses of long bones. We recently assigned the CED locus to an interval between D19S422 and D19S606 at chromosome 19q13.1-q13.3, which two other groups confirmed. As the human transforming growth factor-1 gene (TGFB1) is located within this interval, we considered it a candidate gene for CED.

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Available from: Koh-Ichiro Yoshiura, May 09, 2014
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    • "Genes encoding proteins of the TGF-β signaling pathway [ten Dijke and Arthur, 2007] are implicated in hereditary connective tissue disorders that are associated with arterial aneurysms and dissections (Figure 1) [Boileau et al, 2012; Carmignac et al, 2012; Doyle et al, 2012; Gallione et al, 2004; Howe et al, 1998; Kinoshita et al, 2000; van de Laar et al, 2011; Le Goff et al, 2011; Lindsay et al, 2012; Loeys et al, 2005]. Loeys-Dietz syndrome (LDS) and dominant inheritance of thoracic aortic disease in the absence of LDS features (termed familial thoracic aortic disease; FTAAD) are caused by heterozygous mutations in TGFBR1, TGFBR2, TGFB2 and SMAD3. "
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    ABSTRACT: We report three families with arterial aneurysms and dissections in which variants predicted to be pathogenic were identified in SMAD2. Moreover, one variant occurred de novo in a proband with unaffected parents. SMAD2 is a strong candidate gene for arterial aneurysms and dissections given its role in the TGF-β signaling pathway. Furthermore, although SMAD2 and SMAD3 probably have functionally distinct roles in cell signaling, they are structurally very similar. Our findings indicate that SMAD2 mutations are associated with arterial aneurysms and dissections and are in accordance with the observation, that patients with pathogenic variants in genes encoding proteins involved in the TGF-β signaling pathway, exhibit arterial aneurysms and dissections as key features This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.
    Human Mutation 08/2015; DOI:10.1002/humu.22854 · 5.14 Impact Factor
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    • "TGFB1 is a multifunctional cytokine that is essential for maintaining homeostasis involving bone and the immune response (Watanabe et al., 2002). Mutations that increase TGFB1 activity causes Camurati-Engelmann disease (Kinoshita et al., 2000), a bone-sclerosing disorder, and those in other domains may be associated with osteoporosis (Park et al., 2003). Thys et al., 2007a investigated the implication of TGFB1 in otosclerosis and demonstrated that the amino acid changing SNP T236I was associated with the disease in Dutch–Belgian and French populations. "
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    ABSTRACT: Otosclerosis is a condition characterized by an abnormal bone metabolism in the otic capsule, resulting in conductive and/or sensorineural hearing loss. Otosclerosis is a common disorder in which genes play an important role. Case-control association studies have implicated several genes in the abnormal bone metabolism associated with otosclerosis: COL1A1, TGFB1, BMP2, and BMP4. To investigate the association of these genes with otosclerosis in the Tunisian population, we examined nine single nucleotide polymorphisms (SNPs) in 159 unrelated otosclerosis patients and 155 unrelated controls. We found an association of rs11327935 in COL1A1 with otosclerosis that was shown to be sex specific. The coding polymorphism T263I in TGFB1 was also associated with otosclerosis in the Tunisian population. The effect sizes of both the associations were consistent with previous studies, as the same effect was found in all cases. The association of BMP2 and BMP4 was not significant. However, a trend towards association was found for the BMP4 gene that was consistent with earlier reports. In conclusion, this study replicates and strengthens the evidence for association between polymorphisms of COL1A1 and TGFB1 in the genetic aetiology of otosclerosis.
    Annals of Human Genetics 09/2011; 75(5):598-604. DOI:10.1111/j.1469-1809.2011.00665.x · 2.21 Impact Factor
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    • "In 2000, discovery that TGFβ1 mutation causes CED, together with subsequent family studies, confirmed the disorder's variable expressivity by documenting asymptomatic family members.(43,44) Following reports of higher plasma TGFβ1 levels in individuals with a -509T allele, Campos-Xavier et al.(68) in 2001 investigated whether TGFβ1 polymorphisms explain the variable penetrance of CED. "
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    ABSTRACT: We report a 32-year-old man and his 59-year-old mother with a unique and extensive variant of Camurati-Engelmann disease (CED) featuring histopathological changes of osteomalacia and alterations within TGFβ1 and TNFSF11 encoding TGFβ1 and RANKL, respectively. He suffered leg pain and weakness since childhood and reportedly grew until his late 20s, reaching 7 feet in height. He had deafness, perforated nasal septum, torus palatinus, disproportionately long limbs with knock-knees, low muscle mass, and pseudoclubbing. Radiographs revealed generalized skeletal abnormalities, including wide bones and cortical and trabecular bone thickening in keeping with CED, except that long bone ends were also affected. Lumbar spine and hip BMD Z-scores were + 7.7 and + 4.4, respectively. Biochemical markers of bone turnover were elevated. Hypocalciuria accompanied low serum 25-hydroxyvitamin D (25[OH]D) levels. Pituitary hypogonadism and low serum insulin-like growth factor (IGF)-1 were present. Karyotype was normal. Despite vitamin D repletion, iliac crest histology revealed severe osteomalacia. Exon 1 of TNFRSF11A (RANK), exons 2, 3, and 4 of LRP5, and all coding exons and adjacent mRNA splice junctions of TNFRSF11B (OPG), SQSTM1 (sequestosome 1), and TNSALP (tissue nonspecific alkaline phosphatase) were intact. His asymptomatic and less dysmorphic 5'11″ mother, also with low serum 25(OH)D, had milder clinical, radiological, biochemical, and histopathological findings. Both individuals were heterozygous for a novel 12-bp duplication (c.27_38dup, p.L10_L13dup) in exon 1 of TGFβ1, predicting four additional leucine residues in the latency-associated-peptide segment of TGFβ1, consistent with CED. The son was also homozygous for a single base transversion in TNFSF11, predicting a nonconservative amino acid change (c.107C > G, p.Pro36Arg) in the intracellular domain of RANKL that was heterozygous in his nonconsanguineous parents. This TNFSF11 variant was not found in the SNP Database, nor in published TNFSF11 association studies, but it occurred in four of the 134 TNFSF11 alleles (3.0%) we tested randomly among individuals without CED. Perhaps the unique phenotype of this CED family is conditioned by altered RANKL activity.
    Journal of bone and mineral research: the official journal of the American Society for Bone and Mineral Research 05/2011; 26(5):920-33. DOI:10.1002/jbmr.283 · 6.83 Impact Factor
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