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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    • "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.
    Full-text · Article · Sep 2011 · Annals of Human Genetics
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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.
    Full-text · Article · May 2011 · Journal of bone and mineral research: the official journal of the American Society for Bone and Mineral Research
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    • "The TGFB1 gene, which influences osteoblast and osteoclast function, is thought to act as a coupling factor between bone deposition and resorption (12). In addition, it has been reported that CED is caused by mutations in the gene encoding for TGFB1 (7, 8, 12, 13). With the presence of an activating mutation in the TGFB1 gene, the inhibiting effect of TGFB1 on osteoclast differentiation and activation and its stimulatory effect on osteoblast chemotaxis, proliferation, and differentiation will be enhanced (12). "
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    ABSTRACT: Camurati-Engelmann disease (CED) is an autosomal dominant progressive diaphyseal dysplasia caused by mutations in the transforming growth factor-beta1 (TGFB1) gene. We report the first Korean family with an affected mother and son who were diagnosed with CED. The proband is a 19-yr-old male with a history of abnormal gait since the age of 2. He also suffered from proximal muscle weakness, pain in the extremities, and easy fatigability. Skeletal radiographs of the long bones revealed cortical, periosteal, and endosteal thickenings, predominantly affecting the diaphyses of the upper and lower extremities. No other bony abnormalities were noted in the skull and spine and no remarkable findings were seen on laboratory tests. The patient's mother had a long-standing history of mild limb pain. Under the impression of CED on radiographic studies, we performed mutation analysis. A heterozygous G to A transition at cDNA position +653 in exon 4 of the TGFB1 gene (R218H) was detected in the patient and his mother.
    Full-text · Article · Sep 2009 · Journal of Korean medical science
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