Beaulieu–Boycott–Innes syndrome: an intellectual disability syndrome with characteristic facies

Casey, Jillian P.; Jenkinson, Allan; Magee, Alex; Ennis, Sean; Monavari, Ahmad; Green, Andrew J.; Lynch, Sally Ann; Crushell, Ellen; Hughes, Joanne

doi:10.1097/mcd.0000000000000134

Cited by 13 publications

(19 citation statements)

References 11 publications

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“…b. Location of human disease-associated mutations in THOC2 (Kumar et al, 2020(Kumar et al, , 2018(Kumar et al, , 2015) and THOC6 (Beaulieu et al, 2013;Casey et al, 2016;Anazi et al, 2016;Amos et al, 2017;Mattioli et al, 2019). Several THOC6 mutations were shown to affect its stability and lead to the loss of interaction with THO subunits (Mattioli et al, 2019), suggesting that stabilization of the THO tetramer is needed for its full activity.…”

Section: Model Of Mrna Export Licensingmentioning

confidence: 99%

Structure of the human core transcription-export complex reveals a hub for multivalent interactions

Pühringer

Hohmann

Fin

et al. 2020

eLife

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The export of mRNA from nucleus to cytoplasm requires the conserved and essential transcription and export (TREX) complex (THO–UAP56/DDX39B–ALYREF). TREX selectively binds mRNA maturation marks and licenses mRNA for nuclear export by loading the export factor NXF1–NXT1. How TREX integrates these marks and achieves high selectivity for mature mRNA is poorly understood. Here we report the cryo-electron microscopy structure of the human THO–UAP56/DDX39B complex at 3.3 Å resolution. The seven-subunit THO–UAP56/DDX39B complex multimerizes into a 28-subunit tetrameric assembly, suggesting that selective recognition of mature mRNA is facilitated by the simultaneous sensing of multiple, spatially distant mRNA regions and maturation marks. Two UAP56/DDX39B RNA helicases are juxtaposed at each end of the tetramer, which would allow one bivalent ALYREF protein to bridge adjacent helicases and regulate the TREX–mRNA interaction. Our structural and biochemical results suggest a conserved model for TREX complex function that depends on multivalent interactions between proteins and mRNA.

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Section: Model Of Mrna Export Licensingmentioning

confidence: 99%

Structure of the human core transcription-export complex reveals a hub for multivalent interactions

Pühringer

Hohmann

Fin

et al. 2020

eLife

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“…Facial dysmorphic features are reported in all patients but the overall pattern does not allow a straight gestalt recognition of BBIS. Prenatally detected anomalies were observed in seven patients (Accogli et al, 2018; Amos et al, 2017; Casey et al, 2016; Mattioli et al, 2019) (Table 1) namely FGR (4/7), cerebral malformations (4/7) genito‐renal malformation (2/7) and a cystic hygroma associated with a severe cardiopathy (our patient 2) but cystic hygroma has not been reported yet. In one family (Anazi et al, 2016) a neonatal death associated with congenital heart defect and a stillbirth associated with hydrops fetalis were reported.…”

Section: Discussionmentioning

confidence: 67%

“…Our patients are in agreement with the clinical diagnosis of BBIS characterized by variable phenotype. Including the present family, biallelic THOC6 variants are reported in 17 patients from 12 different BBIS families (Amos et al, 2017; Anazi et al, 2016; Beaulieu et al, 2013; Casey et al, 2016; Gupta et al, 2020; Mattioli et al, 2019; Zhang et al, 2020). The age of the patients ranged from 3 to 22 years.…”

Section: Discussionmentioning

confidence: 75%

“…Facial dysmorphic features are reported in all patients but the overall pattern does not allow a straight gestalt recognition of BBIS. Prenatally detected anomalies were observed in seven patients (Accogli et al, 2018;Amos et al, 2017;Casey et al, 2016;Mattioli et al, 2019) (Table 1) namely FGR (4/7), cerebral malformations (4/7) genito-renal malformation (2/7) and a cystic hygroma associated with a severe cardiopathy (our The neurodevelopmental assessment using the second edition of the Vineland Adaptive Behavior Scales (VABS), showed a composite score of adaptive behavior in the lower zone (NS = 20). She was delayed in four domains: respectively Communication (QD = 18.5), Daily living skills (QD = 16) Socialization (QD = 20) and Motor domains (QD = 18.5).…”

Section: Discussionmentioning

confidence: 98%

“…Beaulieu–Boycott–Innes syndrome (BBIS – OMIM # 613680), was first described in four patients with syndromic intellectual disability (ID) (Beaulieu et al, 2013). To date, THOC6 pathogenic variants were reported in patients presenting moderate to severe ID associated with facial dysmorphic features and severe birth defects (Table 1) (Accogli et al, 2018; Amos et al, 2017; Anazi et al, 2016; Beaulieu et al, 2013; Boycott et al, 2010; Casey et al, 2016; Gupta et al, 2020; Mattioli et al, 2019; Zhang, Chen, Qin, Zheng, & Fan, 2020). BBSI is caused by biallelic loss‐of‐function variants in THOC6 gene (OMIM#613680) (Beaulieu et al, 2013).…”

Section: Introductionmentioning

confidence: 99%

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Biallelic THOC6 pathogenic variants: Prenatal phenotype and review of the literature

Ruaud

Roux

Boutaud

et al. 2022

Birth Defects Research

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Background: The THOC6 protein is a component of the THO complex. It is involved in mRNA transcription, processing and nuclear export. Interestingly molecular biallelic loss-of-function variants of the THOC6 gene were identified in the Beaulieu-Boycott-Innes syndrome (BBIS-OMIM # 613680). This condition was described in 17 patients and is characterized by a moderate to severe intellectual disability, facial dysmorphic features and severe birth defects such as heart, skeletal, ano-genital and renal congenital malformations.Methods: In the present study, we report on a new family with two affected sibs. The 6-year-old female had severe intellectual disability with autistic features, feeding difficulties, growth delay, facial dysmorphic, and congenital malformations (hand, skeletal and cardiac anomalies). The male fetus presented antenatally with a cystic hygroma associated with severe aortic and left ventricular hypoplasia. Autopsy, after termination of pregnancy at 15 weeks of gestation, showed facial dysmorphic, short right thumb and hypospadias.Results: Exome sequencing detected in both sibs compound heterozygous variants of the THOC6 gene (NM_024339.3, GRCh37): the already reported c.[298T>A;700G>T;824G>A] haplotype and a novel variant c.977T>G, p. (Val326Gly).Discussion: We made a review of the literature of 17 BBIS reported patients including our two siblings. Severe to moderate ID and congenital malformations were constant. Prenatal and postnatal failure to thrive were frequent. Brain MRI were not specific. Prenatal findings were reported in 40% of cases but we described the first case of cystic hygroma. The present study reports extends the prenatal delineation of the phenotypic features observed in association with the presence of THOC6 variants. In addition, it underscores the intrafamilial phenotypic variability observed in BBIS.

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Novel CNS malformations and skeletal anomalies in a patient with Beaulieu‐boycott‐Innes syndrome

Accogli

Scala

Calcagno

et al. 2018

American J of Med Genetics Pt A

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THO/TREX (transcription/export) is a conserved eukaryotic complex that plays a crucial role in gene expression and prevents DNA damage during mitosis and meiosis. In mammals, TREX is essential during embryogenesis, determining stem cell fate specification by regulating posttranscriptional self‐renewal and differentiation in several tissues. It is composed of a core called THO, consisting of THOC1, 2, 5, 6, 7, and additional proteins. Bi‐allelic mutations in THOC6 have been associated to Beaulieu–Boycott–Innes syndrome (BBIS), a syndromic form of intellectual disability (ID). To date, nine patients harbouring homozygous or compound heterozygous mutations in THOC6 have been reported. Despite the clinical heterogenity and subtle dysmorphic features in some individuals, distinctive facial features are tall forehead, short and upslanting palpebral fissures, deep set eyes, flat philtrum, and malocclusion. Nonlife threatening congenital anomalies are common, including cardiac and renal malformations, anteriorly displaced anus, cryptorchidism in males, submucous cleft palate, and corpus callosum dysgenesis. Affected patients usually have short stature, mild microcephaly, and mild to moderate ID. Here, we describe an Italian patient with BBIS, carrying two compound heterozygous loss‐of‐function (LoF) variants in THOC6 (c.577C > T, p.R193* and c.792_793delCA, p.V264Vfs*48). In addition to the common phenotype, she displays cerebellar hypoplasia with severe vermian dysgenesis and hydrocephalus due to aqueductal stenosis, multiple skeletal anomalies and hypergonadotropic hypogonadism. Thus, we review the previous cases and discuss the phenotypic spectrum of BBIS, providing further evidence regarding the pivotal role of TREX complex in human development.

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Beaulieu–Boycott–Innes syndrome: an intellectual disability syndrome with characteristic facies

Cited by 13 publications

References 11 publications

Structure of the human core transcription-export complex reveals a hub for multivalent interactions

Structure of the human core transcription-export complex reveals a hub for multivalent interactions

Biallelic THOC6 pathogenic variants: Prenatal phenotype and review of the literature

Novel CNS malformations and skeletal anomalies in a patient with Beaulieu‐boycott‐Innes syndrome

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