title

شکلی از سندروم متابوتیک در همراهی با جهش هائی در ژن DYRK1B

کرامتی, علیرضا and فتح زاده, محسن and گو, گوانگ گونگ and سینگ, راجویر and چوی, موریم and فرامرزی, سعید and مین, شریکانت and کسایی, محمد and سراج زاده فرد, کاظم and هوا, جان and کید, کنت ک and بابایی بیگی, محمدعلی and ملک زاده, رضا and حسینیان, عدالت and بابایی, مسعود and لیفتون, ریچارد پ and مانی, آریا (1393) شکلی از سندروم متابوتیک در همراهی با جهش هائی در ژن DYRK1B. New England Journal of Medicine ــ 370 (20). pp. 1909-1919. شاپا 0028-4793

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Official URL: http://www.nejm.org/doi/full/10.1056/NEJMoa1301824...


Title

A Form of the Metabolic Syndrome Associated with Mutations in DYRK1B

English Abstract

Background Genetic analysis has been successful in identifying causative mutations for individual cardiovascular risk factors. Success has been more limited in mapping susceptibility genes for clusters of cardiovascular risk traits, such as those in the metabolic syndrome. Methods We identified three large families with coinheritance of early-onset coronary artery disease, central obesity, hypertension, and diabetes. We used linkage analysis and whole-exome sequencing to identify the disease-causing gene. Results A founder mutation was identified in DYRK1B, substituting cysteine for arginine at position 102 in the highly conserved kinase-like domain. The mutation precisely cosegregated with the clinical syndrome in all the affected family members and was absent in unaffected family members and unrelated controls. Functional characterization of the disease gene revealed that nonmutant protein encoded by DYRK1B inhibits the SHH (sonic hedgehog) and Wnt signaling pathways and consequently enhances adipogenesis. Furthermore, DYRK1B promoted the expression of the key gluconeogenic enzyme glucose-6-phosphatase. The R102C allele showed gain-of-function activities by potentiating these effects. A second mutation, substituting proline for histidine 90, was found to cosegregate with a similar clinical syndrome in an ethnically distinct family. Conclusions These findings indicate a role for DYRK1B in adipogenesis and glucose homeostasis and associate its altered function with an inherited form of the metabolic syndrome. (Funded by the National Institutes of Health.)

Item Type:Article
زبان سند : انگلیسی
نویسنده اول :علیرضا کرامتی
نویسنده :عدالت حسینیان
Additional Information:IF: 51 Indexing in : (ISI) Science Citation Index , Science Citation Index Expanded , MEDLINE , PubMed , Current Contents - Clinical Medicine , Current Contents - Life Sciences , BIOSIS Previews , Index medicus , Abridged index medicus , OLDMEDLINE
کلیدواژه ها (انگلیسی):Metabolic Syndrome , DYRK1B
Subjects:QZ Pathology
WG Cardiovascular System
WI Digestive System
Divisions:Faculty of Medicine > Department of Internal Medicine , Cardiology , Infectious
ID Code:6166
Deposited By: MS Soghra Golmaghani
Deposited On:23 Sep 1393 09:55
Last Modified:24 Sep 1393 04:06

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