scholarly journals Thalidomide promotes degradation of SALL4, a transcription factor implicated in Duane Radial Ray syndrome

eLife ◽  
2018 ◽  
Vol 7 ◽  
Author(s):  
Katherine A Donovan ◽  
Jian An ◽  
Radosław P Nowak ◽  
Jingting C Yuan ◽  
Emma C Fink ◽  
...  
Keyword(s):  
Congenital Heart Disease ◽  
Transcription Factor ◽  
Transcription Factors ◽  
Birth Defects ◽  
Molecular Basis ◽  
Congenital Heart ◽  
Loss Of Function ◽  
Morning Sickness ◽  
Species Specific ◽  
Developmental Condition

In historical attempts to treat morning sickness, use of the drug thalidomide led to the birth of thousands of children with severe birth defects. Despite their teratogenicity, thalidomide and related IMiD drugs are now a mainstay of cancer treatment; however, the molecular basis underlying the pleiotropic biology and characteristic birth defects remains unknown. Here we show that IMiDs disrupt a broad transcriptional network through induced degradation of several C2H2 zinc finger transcription factors, including SALL4, a member of the spalt-like family of developmental transcription factors. Strikingly, heterozygous loss of function mutations in SALL4 result in a human developmental condition that phenocopies thalidomide-induced birth defects such as absence of thumbs, phocomelia, defects in ear and eye development, and congenital heart disease. We find that thalidomide induces degradation of SALL4 exclusively in humans, primates, and rabbits, but not in rodents or fish, providing a mechanistic link for the species-specific pathogenesis of thalidomide syndrome.

scholarly journals Rescue of a developmental arrest caused by a C. elegans heat-shock transcription-factor mutation by loss of ribosomal S6-kinase activity

2018 ◽  
Author(s):  
Peter Chisnell ◽  
T. Richard Parenteau ◽  
Elizabeth Tank ◽  
Kaveh Ashrafi ◽  
Cynthia Kenyon
Keyword(s):  
Transcription Factor ◽  
Transcription Factors ◽  
Heat Shock ◽  
Heat Shock Transcription Factor ◽  
Adult Longevity ◽  
Loss Of Function ◽  
S6 Kinase ◽  
Heat Shock Transcription Factors ◽  
C Elegans ◽  
Developmental Arrest

AbstractThe widely conserved heat-shock response, regulated by heat shock transcription factors, is not only essential for cellular stress resistance and adult longevity, but also for proper development. However, the genetic mechanisms by which heat-shock transcription factors regulate development are not well understood. In C. elegans, we conducted an unbiased genetic screen to identify mutations that could ameliorate the developmental arrest phenotype of a heat-shock factor mutant. Here we show that loss of the conserved translational activator rsks-1/S6-Kinase, a downstream effector of TOR kinase, can rescue the developmental-arrest phenotype of hsf-1 partial loss-of-function mutants. Unexpectedly, we show that the rescue is not likely caused by reduced translation, nor to activation of any of a variety of stress-protective genes and pathways. Our findings identify an as-yet unexplained regulatory relationship between the heat-shock transcription factor and the TOR pathway during C. elegans’ development.

Twins

2019 ◽  
pp. 25-30
Author(s):  
Robin D. Clark ◽  
Cynthia J. Curry
Keyword(s):  
Risk Factors ◽  
Congenital Heart Disease ◽  
Heart Disease ◽  
Birth Defects ◽  
Congenital Heart ◽  
Clinical Case ◽  
Monozygotic Twins ◽  
Perinatal Complications ◽  
Case Presentation ◽  
Incidence Risk

This chapter reviews the incidence, risk factors, and epidemiology of disorders associated with twinning. The timing of twinning and the types of twins are reviewed. The fetal and perinatal complications of twinning including twin to twin transfusion and its treatment are discussed, as well as the possible consequences of death of a monozygotic co-twin. These include severe disruptive brain abnormalities, and other vascular disruptive defects. The birth defects more common in twins are enumerated and specific patterns of birth defects such as hemifacial macrosomia and VACTERL are discussed. A clinical case presentation features monozygotic twins with twin-to-twin transfusion syndrome and congenital heart disease.

scholarly journals Loss of function and inhibitory effects of human CSX/NKX2.5 homeoprotein mutations associated with congenital heart disease

2000 ◽  
Vol 106 (2) ◽  
pp. 299-308 ◽  
Author(s):  
Hideko Kasahara ◽  
Bora Lee ◽  
Jean-Jacques Schott ◽  
D. Woodrow Benson ◽  
J.G. Seidman ◽  
...  
Keyword(s):  
Congenital Heart Disease ◽  
Heart Disease ◽  
Congenital Heart ◽  
Loss Of Function ◽  
Inhibitory Effects

scholarly journals Association between early prenatal exposure to ambient air pollution and birth defects: evidence from newborns in Xi’an, China

2018 ◽  
Vol 41 (3) ◽  
pp. 494-501 ◽  
Author(s):  
Lingling Wang ◽  
Xiaomei Xiang ◽  
Baibing Mi ◽  
Hui Song ◽  
Min Dong ◽  
...  
Keyword(s):  
Congenital Heart Disease ◽  
Heart Disease ◽  
Cleft Palate ◽  
Birth Defects ◽  
Air Pollutants ◽  
Congenital Heart ◽  
Ambient Air ◽  
Ambient Air Pollution ◽  
Ambient Air Pollutants ◽  
Increased Risk

Abstract Background The aim of this study was to investigate an association between birth defects and exposure to sulfur dioxide (SO2), nitrogen dioxide (NO2) and particles ≤10 μm in an aerodynamic diameter (PM10) during early pregnancy in Xi’an, China. Methods Birth defect data were from the Birth Defects Monitoring System of Xi’an, and data on ambient air pollutants during 2010–15 were from the Xi’an Environmental Protection Bureau. A generalized additive model (GAM) was used to investigate the relationship between birth defects and ambient air pollutants. Results Among the 8865 cases with birth defects analyzed, the overall incidence of birth defects was 117.33 per 10 000 infants. Ambient air pollutant exposure during the first trimester increased the risk of birth defects by 10.3% per 10 μg/m3 increment of NO2 and 3.4% per 10 μg/m3 increment of PM10. No significant association was found between birth defects and SO2. Moreover, NO2 increased risk of neural tube defects, congenital heart disease, congenital polydactyly, cleft palate, digestive system abnormalities and gastroschisis, and PM10 was associated with congenital heart disease and cleft lip with or without cleft palate. Conclusions Chinese women should avoid exposure to high levels of NO2 and PM10 during the first 3 months of pregnancy.

Mutations in EKLF/KLF1 form the molecular basis of the rare blood group In(Lu) phenotype

Blood ◽  
2008 ◽  
Vol 112 (5) ◽  
pp. 2081-2088 ◽  
Author(s):  
Belinda K. Singleton ◽  
Nicholas M. Burton ◽  
Carole Green ◽  
R. Leo Brady ◽  
David J. Anstee
Keyword(s):  
Transcription Factor ◽  
Blood Group ◽  
Molecular Basis ◽  
Zinc Finger Domain ◽  
Loss Of Function ◽  
Conserved Residues ◽  
Transcript Levels ◽  
Premature Termination Codons ◽  
B Blood Group ◽  
Inactivating Mutations

Abstract Comparison of normal erythroblasts and erythroblasts from persons with the rare In(Lu) type of Lu(a-b-) blood group phenotype showed increased transcription levels for 314 genes and reduced levels for 354 genes in In(Lu) cells. Many erythroid-specific genes (including ALAS2, SLC4A1) had reduced transcript levels, suggesting the phenotype resulted from a transcription factor abnormality. A search for mutations in erythroid transcription factors showed mutations in the promoter or coding sequence of EKLF in 21 of 24 persons with the In(Lu) phenotype. In all cases the mutant EKLF allele occurred in the presence of a normal EKLF allele. Nine different loss-of-function mutations were identified. One mutation abolished a GATA1 binding site in the EKLF promoter (−124T>C). Two mutations (Leu127X; Lys292X) resulted in premature termination codons, 2 (Pro190LeufsX47; Arg319GlufsX34) in frameshifts, and 4 in amino acid substitution of conserved residues in zinc finger domain 1 (His299Tyr) or domain 2 (Arg328Leu; Arg328His; Arg331Gly). Persons with the In(Lu) phenotype have no reported pathology, indicating that one functional EKLF allele is sufficient to sustain human erythropoiesis. These data provide the first description of inactivating mutations in human EKLF and the first demonstration of a blood group phenotype resulting from mutations in a transcription factor.

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