Human TBX1 Missense Mutations Cause Gain of Function Resulting in the Same Phenotype as 22q11.2 Deletions
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TLDR
It is concluded that TBX1 gain-of-function mutations can result in the same phenotypic spectrum as haploinsufficiency caused by loss of function mutations or deletions.Abstract:
Deletion 22q11.2 syndrome is the most frequent known microdeletion syndrome and is associated with a highly variable phenotype, including DiGeorge and Shprintzen (velocardiofacial) syndromes. Although haploinsufficiency of the T-box transcription factor gene TBX1 is thought to cause the phenotype, to date, only four different point mutations in TBX1 have been reported in association with six of the major features of 22q11.2 deletion syndrome. Although, for the two truncating mutations, loss of function was previously shown, the pathomechanism of the missense mutations remains unknown. We report a novel heterozygous missense mutation, H194Q, in a familial case of Shprintzen syndrome and show that this and the two previously reported missense mutations result in gain of function, possibly through stabilization of the protein dimer DNA complex. We therefore conclude that TBX1 gain-of-function mutations can result in the same phenotypic spectrum as haploinsufficiency caused by loss-of-function mutations or deletions.read more
Citations
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Journal ArticleDOI
22q11.2 deletion syndrome
Donna M. McDonald-McGinn,Kathleen E. Sullivan,Bruno Marino,Nicole Philip,Ann Swillen,Jacob A. S. Vorstman,Elaine H. Zackai,Beverly S. Emanuel,Joris Vermeesch,Bernice E. Morrow,Peter J. Scambler,Anne S. Bassett +11 more
TL;DR: The first description in the English language of the constellation of findings now known to be due to this chromosomal difference was made in the 1960s in children with DiGeorge syndrome, who presented with the clinical triad of immunodeficiency, hypoparathyroidism and congenital heart disease as mentioned in this paper.
Journal Article
The 22q11.2 deletion syndrome.
TL;DR: 22q11.2 deletion syndrome is now known to have a heterogeneous presentation that includes multiple additional congenital anomalies and later-onset conditions, such as palatal, gastrointestinal and renal abnormalities, autoimmune disease, variable cognitive delays, behavioural phenotypes and psychiatric illness — all far extending the original description of DiGeorge syndrome.
Journal ArticleDOI
Clinical practice. Hypoparathyroidism.
TL;DR: A 58-year-old man is found on laboratory testing to have a serum calcium level of 6.0 mg per deciliter (1.5 mmol per liter) and his medical history is notable only for longstanding hearing difficulties.
Journal ArticleDOI
Genetics of Congenital Heart Disease
TL;DR: How the advent of contemporary genomic technologies including single nucleotide polymorphism arrays, next-generation sequencing, and copy number variant platforms are accelerating the discovery of genetic causes of CHD is explored.
Journal ArticleDOI
Chromosome 22q11.2 deletion syndrome (DiGeorge syndrome/velocardiofacial syndrome).
TL;DR: Chromosome 22q11.2 deletion syndrome is a common syndrome also known as DiGeorge syndrome and velocardiofacial syndrome, and the incidence is increasing due to affected parents bearing their own affected children.
References
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Journal ArticleDOI
A Common Molecular Basis for Rearrangement Disorders on Chromosome 22q11
Lisa Edelmann,Raj K. Pandita,Elizabeth Spiteri,Birgit Funke,Rosalie Goldberg,Nallasivam Palanisamy,R. S. K. Chaganti,Ellen Magenis,Robert J. Shprintzen,Bernice E. Morrow +9 more
TL;DR: Models are presented to explain how the LCR22s can mediate different homologous recombination events, thereby generating a number of rearrangements that are associated with congenital anomaly disorders.
Journal ArticleDOI
Microduplication 22q11.2, an Emerging Syndrome: Clinical, Cytogenetic, and Molecular Analysis of Thirteen Patients
Regina Ensenauer,Adewale Adeyinka,Heather C. Flynn,Virginia V. Michels,Noralane M. Lindor,D. Brian Dawson,Erik C. Thorland,Cindy Pham Lorentz,Jennifer L. Goldstein,Marie T. McDonald,Wendy E. Smith,Elba Simon-Fayard,Alan A. Alexander,Anita S. Kulharya,Rhett P. Ketterling,Robin D. Clark,Syed M. Jalal +16 more
TL;DR: 13 patients' phenotypes ranged from mild to severe, sharing a tendency for velopharyngeal insufficiency with DG/VCFS but having other distinctive characteristics, as well, and the microduplication of 22q11.2 appears to be a new syndrome.
Journal ArticleDOI
Crystallographic structure of the T domain-DNA complex of the Brachyury transcription factor.
TL;DR: The structure of this T domain complex with DNA reveals a new way in which a protein can recognize DNA, as well as revealing a new type of specific DNA contact.
Journal ArticleDOI
Tbx1 haploinsufficiency is linked to behavioral disorders in mice and humans: implications for 22q11 deletion syndrome.
Richard Paylor,Beate Glaser,Annalisa Mupo,Paris Ataliotis,Corinne M. Spencer,Angela Sobotka,Chelsey Sparks,Chul-Hee Choi,John S. Oghalai,Sarah Curran,Kieran C. Murphy,Stephen Monks,Nigel Williams,Michael Conlon O'Donovan,Michael John Owen,Peter J. Scambler,Elizabeth A. Lindsay +16 more
TL;DR: It is shown that PPI deficits in Df1/+ mice are caused by haploinsufficiency of two genes, Tbx1 and Gnb1l, which are strong candidates for psychiatric disease in 22q11DS patients and candidate susceptibility genes in the wider population.
Journal ArticleDOI
COMT genotype predicts longitudinal cognitive decline and psychosis in 22q11.2 deletion syndrome.
Doron Gothelf,Doron Gothelf,Stephan Eliez,Tracy Thompson,Christine Hinard,Lauren Penniman,Carl Feinstein,Hower Kwon,Shuting Jin,Booil Jo,Stylianos E. Antonarakis,Michael A. Morris,Allan L. Reiss +12 more
TL;DR: This longitudinal study of adolescents with 22q11.2 deletion syndrome identified the catechol-O-methyltransferase low-activity allele (COMTL) as a risk factor for decline in prefrontal cortical volume and cognition, as well as for the consequent development of psychotic symptoms during adolescence.
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