Identification of a novel NOG gene mutation (P35S) in an Italian family with symphalangism

C.S.S. Mendel Institute and University La Sapienza, Rome, Italy.
Human Mutation (Impact Factor: 5.14). 03/2002; 19(3):308. DOI: 10.1002/humu.9016
Source: PubMed


Symphalangism (SYM or SYM1) is an autosomal dominant disorder characterized by multiple joint fusions. The disease is caused by mutations of the NOG gene, that maps to chromosome 17q22. So far, only six independent NOG mutations have been identified. We have analysed an Italian family in which father and son had bilateral symphalangism and detected a novel NOG mutation (P35S), originated in the father from a c.914C>T transition. A different mutation in the same codon (P35R) has been previously described. Comparison between different noggin gene hortologs shows that codon 35 is conserved. Therefore, this codon should play an important role in NOG gene function. This is the first mutation described for NOG after the initial report of NOG mutations being causative of SYM.

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    • "Decreased affinity for BMP; prevents interaction with BMP type I receptors c.103C4T p.Pro35Ser Missense SABTT Hirshoren et al., 2008 Conformational change; prevents interaction with BMP type I receptors BDB2 Lehmann et al., 2007 SYM1 Mangino et al., 2002 c.104C4G p.Pro35Arg Missense SYM1 Gong et al., 1999 Conformational change; prevents interaction with BMP type I receptors TCC Dixon et al., 2001 c.106G4C p.Ala36Pro Missense BDB2 Lehmann et al., 2007 Conformational change; prevents interaction with BMP type I receptors c.110C4G p.Pro37Arg Missense TCC Debeer et al., 2004 Destruction of beta-sheet motif and conformational change; prevents interaction with BMP type I receptors c.[124C4G; 149C4G] p.[Pro42Ala; Pro50Arg] Double missense mutation SYNS1 Debeer et al., 2004 "
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    ABSTRACT: The NOG gene encodes noggin, a secreted polypeptide that is important for regulating multiple signaling pathways during human development, particularly in cartilage and bone. The hallmark of NOG-related syndromes is proximal symphalangism, defined by abnormal fusion of the proximal interphalangeal joints of the hands and feet. Many additional features secondary to NOG mutations are commonly but inconsistently observed, including a characteristic facies with a hemicylindrical nose, congenital conductive hearing loss due to stapes fixation, and hyperopia. The variable clinical presentations led to the designation of five different autosomal dominant syndromes, all subsequently found to have resulted from NOG mutations. These include (1) proximal symphalangism; (2) multiple synostoses syndrome 1; (3) stapes ankylosis with broad thumbs and toes; (4) tarsal-carpal coalition syndrome; and (5) brachydactyly type B2. Herein, we review the phenotypic features associated with mutations in the NOG gene, demonstrating the overlapping characteristics of these syndromes. Due to the variable phenotypic spectrum within families and among families with the same mutation, we propose a unifying term, NOG-related symphalangism spectrum disorder (NOG-SSD), to aid in the clinical recognition and evaluation of all affected individuals with these phenotypes. These NOG gene variants are available in a new locus-specific database (
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    • "In addition, heterozygosity for mutations in NOGGIN has been identified in stapes ankylosis syndrome without symphalangism (MIM 184460) (Brown et al. 2002). To date, 14 distinct NOG- GIN mutations have been reported (Gong et al. 1999; Dixon et al. 2001; Takahashi et al. 2001; Brown et al. 2002; Mangino et al. 2002). The majority (10 of 14) are missense mutations, and the 4 nonsense mutations are predicted to result in premature translation termination codons. "
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    ABSTRACT: Multiple-synostosis syndrome is an autosomal dominant disorder characterized by progressive symphalangism, carpal/tarsal fusions, deafness, and mild facial dysmorphism. Heterozygosity for functional null mutations in the NOGGIN gene has been shown to be responsible for the disorder. However, in a cohort of six probands with multiple-synostosis syndrome, only one was found to be heterozygous for a NOGGIN mutation (W205X). Linkage studies involving the four-generation family of one of the mutation-negative patients excluded the NOGGIN locus, providing genetic evidence of locus heterogeneity. In this family, polymorphic markers flanking the GDF5 locus were found to cosegregate with the disease, and sequence analysis demonstrated that affected individuals in the family were heterozygous for a novel missense mutation that predicts an R438L substitution in the GDF5 protein. Unlike mutations that lead to haploinsufficiency for GDF5 and produce brachydactyly C, the protein encoded by the multiple-synostosis-syndrome allele was secreted as a mature GDF5 dimer. These data establish locus heterogeneity in multiple-synostosis syndrome and demonstrate that the disorder can result from mutations in either the NOGGIN or the GDF5 gene.
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