Mutations of the <i>NOG</i> gene in individuals with proximal symphalangism and multiple synostosis syndrome

Takahashi, Tsutomu; Takahashi, Ikuko; Komatsu, Masaki; Sawaishi, Yukio; Higashi, Koichiro; Nishimura, Gen; Saito, Hiuga; Takada, Goro

doi:10.1034/j.1399-0004.2001.600607.x

Cited by 87 publications

(73 citation statements)

References 7 publications

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“…[25][26][27][28][29] Two previously reported 17q22 microdeletion, patients were intellectually disabled. 7,8 All patients in our study, including patient 6, have intellectual disability and deletions of NOG and C17ORF67.…”

Section: Discussionmentioning

confidence: 99%

Molecular and clinical delineation of the 17q22 microdeletion phenotype

et al. 2013

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Deletions involving 17q21-q24 have been identified previously to result in two clinically recognizable contiguous gene deletion syndromes: 17q21.31 and 17q23.1-q23.2 microdeletion syndromes. Although deletions involving 17q22 have been reported in the literature, only four of the eight patients reported were identified by array-comparative genomic hybridization (array-CGH) or flourescent in situ hybridization. Here, we describe five new patients with 1.8-2.5-Mb microdeletions involving 17q22 identified by array-CGH. We also present one patient with a large karyotypically visible deletion involving 17q22, fine-mapped to B8.2 Mb using array-CGH. We show that the commonly deleted region in our patients spans 0.24 Mb and two genes; NOG and C17ORF67. The function of C17ORF67 is not known, whereas Noggin, the product of NOG, is essential for correct joint development. In common with the 17q22 patients reported previously, the disease phenotype of our patients includes intellectual disability, attention deficit hyperactivity disorder, conductive hearing loss, visual impairment, low set ears, facial dysmorphology and limb anomalies. All patients displayed NOG-related bone and joint features, including symphalangism and facial dysmorphology. We conclude that these common clinical features indicate a novel clinically recognizable, 17q22 contiguous microdeletion syndrome.

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Section: Discussionmentioning

confidence: 99%

Molecular and clinical delineation of the 17q22 microdeletion phenotype

et al. 2013

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“…Multiple synostosis syndrome is also autosomal dominant and is characterized by progressive multiple joint ankylosis and fusion which involves the phalanges, carpal and tarsal bones, as well as the spine [15]. It has been shown that these two disorders in humans are often the result of a mutation in the Noggin gene [8,16,19,30]. This evidence suggests that Noggin, may not only be necessary to limit BMP action in development, but also may be necessary for the maintenance of joint space into adulthood.…”

Section: Discussionmentioning

confidence: 99%

Molecular signaling in intervertebral disk development

DiPaola

Farmer

Manova

et al. 2005

Journal Orthopaedic Research

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The purpose of this investigation is to identify and study the expression pattern of pertinent molecular factors involved in the differentiation of the intervertebral disk (IVD). It is likely that hedgehog genes and the BMP inhibitors are key factors involved in spinal joint formation. Radioactive in situ hybridization with mRNA probes for pax-1, SHH, IHH and Noggin gene was performed on mouse embryo and adult tissue. Immunohistochemistry was performed to localize hedgehog receptor, "patched" (ptc). From 14.5 dpc until birth pax-1 mRNA was expressed in the developing anulus fibrosus (AF). During the same developmental period Noggin mRNA is highly expressed throughout the spine, in the developing AF, while ptc protein and SHH mRNA were expressed in the developing nucleus pulposus (NP). IHH mRNA was expressed by condensing chondrocytes of the vertebral bodies and later becomes confined to the vertebral endplate. We show for the first time that pax-I is expressed in the adult intervertebral disk. Ptc expression in the NP is an indicator of hedgehog protein signaling in the developing IVD. The expression pattern of the BMP inhibitor Noggin appears to be important for the normal formation of the IVD and may prove to play a role in its segmental pattern formation.

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“…These syndromes were shown to be caused by mutations in the BMP antagonist NOG-GIN (NOG; Gong et al, 1999;Dixon et al, 2001;Takahashi et al, 2001;Brown et al, 2002) indicating that inhibition of BMP signaling is pivotal for the process of joint formation. Corroborating this, disruption of the mouse Noggin gene results in enlarged condensations and joint fusions (Brunet et al, 1998).…”

Section: Segmentation Of the Digitsmentioning

confidence: 99%

Mechanisms of digit formation: Human malformation syndromes tell the story

Stricker

Mundlos

2011

Developmental Dynamics

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Identifying the genetic basis of human limb malformation disorders has been instrumental in improving our understanding of limb development. Abnormalities of the hands and/or feet include defects affecting patterning, establishment, elongation, and segmentation of cartilaginous condensations, as well as growth of the individual skeletal elements. While the phenotype of such malformations is highly diverse, the mutations identified to date cluster in genes implicated in a limited number of molecular pathways, namely hedgehog, Wnt, and bone morphogenetic protein. The latter pathway appears to function as a key molecular network regulating different phases of digit and joint development. Studies in animal models not only extended our insight into the pathogenesis of these conditions, but have also contributed to our understanding of the in vivo functions and interactions of these key players. This review is aimed at integrating the current understanding of human digit malformations into the increasing knowledge of the molecular mechanisms of digit development. Developmental Dynamics 240:990-1004,

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Mutations of the NOG gene in individuals with proximal symphalangism and multiple synostosis syndrome

Cited by 87 publications

References 7 publications

Molecular and clinical delineation of the 17q22 microdeletion phenotype

Molecular and clinical delineation of the 17q22 microdeletion phenotype

Molecular signaling in intervertebral disk development

Mechanisms of digit formation: Human malformation syndromes tell the story

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