Dyskeratosis congenita

Bessler, Monica; Wilson, David B.; Mason, Philip J.

doi:10.1016/j.febslet.2010.05.019

Cited by 74 publications

(58 citation statements)

References 72 publications

(96 reference statements)

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“…However, we did detect many sites throughout the protein that contained 2 out of 4 matches to the consensus sequence. Of particular interest was the most C-terminal (potential) site at amino acid position 283 in TIN2 comprising PTVMLFP, since it falls within the cluster of amino acids that are mutated in TIN2-associated dyskeratosis congenita (42,50), an inherited bone marrow failure syndrome that is caused by defects in telomere maintenance (6). We showed recently that the PTVML sequence at position 283 constituted a binding site for heterochromatin protein 1 (10).…”

Section: And C [Shorter Exposure])mentioning

confidence: 99%

TIN2 Stability Is Regulated by the E3 Ligase Siah2

Bhanot

Smith

2012

Molecular and Cellular Biology

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Telomeres are coated by shelterin, a six-subunit complex that is required for protection and replication of chromosome ends. The central subunit TIN2, with binding sites to three subunits (TRF1, TRF2, and TPP1), is essential for stability and function of the complex. Here we show that TIN2 stability is regulated by the E3 ligase Siah2. We demonstrate that TIN2 binds to Siah2 and is ubiquitylated in vivo. We show using purified proteins that Siah2 acts as an E3 ligase to directly ubiquitylate TIN2 in vitro. Depletion of Siah2 led to stabilization of TIN2 protein, indicating that Siah2 regulates TIN2 protein levels in vivo. Overexpression of Siah2 in human cells led to loss of TIN2 at telomeres that was dependent on the presence of the catalytic RING domain of Siah2. In contrast to RNAi-mediated depletion of TIN2 that led to loss of TRF1 and TRF2 at telomeres, Siah2-mediated depletion of TIN2 allowed TRF1 and TRF2 to remain on telomeres, indicating a different fate for shelterin subunits when TIN2 is depleted posttranslationally. TPP1 was lost from telomeres, although its protein level was not reduced. We speculate that Siah2-mediated removal of TIN2 may allow dynamic remodeling of the shelterin complex and its associated factors during the cell cycle.

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Section: And C [Shorter Exposure])mentioning

confidence: 99%

TIN2 Stability Is Regulated by the E3 Ligase Siah2

Bhanot

Smith

2012

Molecular and Cellular Biology

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“…Tırnak-larda pitting, fissürler, incelme, ayrışma, longitudinal oluklanma, pterjiyum ve tırnak atrofisi görülmektedir. 23,32 Birçok olguda X'e bağlı resesif olarak kalıtılmaktadır. Hastaların neredeyse yarı-sında kemik iliği yetmezliği gelişmektedir.…”

Section: Di̇skeratozi̇s Konjeni̇taunclassified

“…Klinik bulgular erişkinlerde-kine benzer, ancak çocuklarda daha hafif şid-dettedir ve genellikle hasta ve ailesi tarafından göz ardı edilmektedir. 32 Tırnaklarda pitting, tırnak plağında skuamların birikmesi ile ayak başparmak tır-nağının kalınlaşması ve subungual hiperkeratoz çocuklarda sık görülen bulgulardır. Psoriatik pittingler genellikle büyük, derin ve düzensiz sınırlı-dır.…”

Section: Psöri̇yazi̇sunclassified

“…Ayak tırnağında kalınlaşma tek veya fazla sayıda tırnağı tutabilmektedir ve matriks psöriya-zisi ya da tırnak yatağı hiperkeratozuna bağlı geliş-mektedir. 5,32 Ayırıcı tanıda onikomikozun dışlan-ması gerekmektedir. Çocuklarda tedavide üre içe-ren kremler tırnak kalınlığını azaltmada tercih edilirken, streoid ve kalsipotriol kombinasyonları ise tırnak yatağı tutulumunda tercih edilmektedir.…”

Section: Psöri̇yazi̇sunclassified

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Nail Diseases in Children: Review

Baykal¹,

Arıca²

2015

Turkiye Klinikleri J Dermatol

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Çocuklarda Görülen Tırnak Hastalıkları Ö ÖZ ZE ET T Çocuklarda tırnak hastalıklarının tanı alması kolay olmamaktadır. Tırnak muayenesi çocuklarda fizik muayenenin önemli bir parçasıdır. Tırnak hastalıkları fizyolojik değişiklikler, konjenital ve kalıtsal durumlar, dermatolojik hastalıklar, tümörler, enfeksiyonlar, travmatik değişiklikler, sistemik veya iyatrojenik nedenler olarak yedi başlık altında incelenebilir. Beau çizgileri, koilonişi, onikoşizi gibi fizyolojik değişiklikler genellikle yaş ile birlikte geriler ve tedavi gerektirmez. Konjenital hastalıklardan tırnak patella sendromunda üçgen şeklinde lunula görülmesi, hastalık için patognomoniktir. Anonişi ve mikronişi izole olabilir ya da çeşitli kompleks sendromların bir parçası olabilir. En sık görülen enfeksiyon, tırnak çevresi yerleşimli siğillerdir. Dermatolojik hastalıklar psöriyazis, liken planus, parakeratozis püstüloza, trakionişi ve liken striatusu kapsamaktadır. Parakeratozis püstüloza ve liken striatus ise tipik olarak çocuk populasyonda izlenmektedir. Tümörler çocuklarda nadiren gö-rülmektedir. Subungual ekzositoz tanısı radyografik değerlendirme ile konulabilir. Çocuklarda longitudinal melanonişilerin %75'i iyi huylu melanositik hiperplaziye bağlı gelişmektedir. Akut tırnak travmaları ve bunların sekelleri pediatrik tırnak konsültasyonlarının en sık nedenleridir. Hastalar sık-lıkla erken çocukluk çağda travmalar sonucu uygunsuz tedavi edilmeye bağlı gelişen geç dönem tır-nak distrofileri için başvurmaktadır. Onikofaji ve onikotillomani kronik travmadan sorumludur. Bu çalışmada, çocuklarda görülen tırnak hastalıkları ve tedavi seçenekleri sunulmuştur.A An na ah h t ta ar r K Ke e l li i m me e l le er r: : Tırnak hastalıkları; çocuk A AB BS S T TR RA AC CT T Nail diseases in children are not easy to diagnose. The examination of nail is an important part of the pediatric physical examination. We can consider nail disorder into seven categories as physiologic alterations, congenital and inherited conditions, infections, dermatologic disorders, tumors, trauma and systemic or iatrogenic nail alterations. Physiologic alterations like beau lines, koilonychia and onychoschizia usually disappear with age and do not require treatment. In congenital disorder nail patella sendrom; triangular lunula is patognomonic for the disease. Anonychia and micronychia can be isolated or part of various complex syndromes. The most common infection is the periungal wart. Dermatologic diseases includes psoriasis, lichen planus, parakeratosis pustulosa, trachyonychia and lichen striatus. Parakeratosis pustulosa and lichen striatus are typically seen in pediatric population. Tumors are rare in children. Subungal exostosis can be diagnosed with radiographic examination. In children; %75 of longitudinal melanonychia is due to benign melanocytic hyperplasia. Acute nail trauma and their sequelae are common cause of pediatric nail consultation. Too often patients ask for help for late dystrophies caused by inadequate management of a nail trauma. Onychophagia and onchotillomani...

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“…Defects in telomere maintenance can have severe consequences for human health, as evidenced by the genetic disease dyskeratosis congenita (DC). 7 DC is caused by mutations in telomerase subunits, resulting in very short telomeres in highly proliferating tissues. 8,9 DC patients suffer stem cell depletion and die of bone marrow stem cell failure.…”

Section: Introductionmentioning

confidence: 99%

A role for sister telomere cohesion in telomere elongation by telomerase

Houghtaling

Canudas²,

Smith

2012

Cell Cycle

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T elomere length homeostasis is achieved by a balance of telomere shortening caused by DNA replication and nucleolytic attack and telomere lengthening by telomerase. The importance of telomere length maintenance to human health is best illustrated by dyskeratosis congenita (DC), a disease of telomere shortening caused by mutations in telomerase subunits. DC patients suffer stem cell depletion and die of bone marrow stem cell failure. Recently a new class of particularly severe DC patients was found to harbor mutations in the shelterin subunit TIN2. The DC-TIN2 mutations were clustered in small domain of unknown function. In a recently published study we showed that the DC mutation cluster in TIN2 harbored a binding site for heterochromatin protein 1 (HP1) and, further, that HP1 binding to TIN2 was required for sister telomere cohesion in S phase and for telomere length maintenance by telomerase. We briefly review and discuss the implications of our findings in this Extra View and present some new data that may shed light on how sister telomere cohesion could influence telomere elongation by telomerase.

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Dyskeratosis congenita

Cited by 74 publications

References 72 publications

TIN2 Stability Is Regulated by the E3 Ligase Siah2

TIN2 Stability Is Regulated by the E3 Ligase Siah2

Nail Diseases in Children: Review

A role for sister telomere cohesion in telomere elongation by telomerase

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