ABSTRACT
Soot samples from different fuels were produced in small and pilot combustion test benches at various O2 concentrations, and were then characterized in terms of primary particle diameter, specific surface area and oxygen content/speciation. Water sorption measurements were then carried out for soot compacted into pellet form and in powder form, using both a gravimetric microbalance and a manometric analyser. Water adsorption isotherms are all found to be Type V, and reveal the central role of the specific surface area and the oxygen content of soot. A single parametrization of the second Dubinin-Serpinsky model gives a proper fit for all isotherms. To the best of our knowledge, this is the first study to provide physico-chemical parameters and water sorption results for fire soot. This enables a better description of the soot cake formed on filters during a fire, in particular in industrial confined facilities as simulated in this study. Humidity can be then explicitly considered in the same way as other parameters influencing the aeraulic resistance of soot cakes. These results can be used to improve predictions of the consequences of fires on the containment of toxic materials within industrial facilities.
ABSTRACT
Multicopper oxidases (MCOs) catalyze the oxidation of a variety of substrates while reducing oxygen into water through four copper atoms. As an additional feature, some MCOs display an enhanced activity in solution in the presence of Cu2+. This is the case of the hyperthermophilic laccase HB27 from Thermus thermophilus, the physiologic role of which is unknown. As a particular feature, this enzyme presents a methionine rich domain proposed to be involved in copper interaction. In this work, laccase from T. thermophilus was produced in E. coli, and the effect of Cu2+ on its electroactivity at carbon nanotube modified electrodes was investigated. Direct O2 electroreduction is strongly dictated by carbon nanotube surface chemistry in accordance with the enzyme dipole moment. In the presence of Cu2+, an additional low potential cathodic wave occurs, which was never described earlier. Analysis of this wave as a function of Cu2+ availability allows us to attribute this wave to a cuprous oxidase activity displayed by the laccase and induced by copper binding close to the Cu T1 center. A mutant lacking the methionine-rich hairpin domain characteristic of this laccase conserves its copper activity suggesting a different site of copper binding. This study provides new insight into the copper effect in methionine rich MCOs and highlights the utility of the electrochemical method to investigate cuprous oxidase activity and to understand the physiological role of these MCOs.
Subject(s)
Copper/metabolism , Electrodes , Laccase/metabolism , Oxygen/metabolism , Thermus thermophilus/metabolism , Oxidation-ReductionABSTRACT
CHARGE syndrome (CS) is a genetic disorder whose first description included Coloboma, Heart disease, Atresia of choanae, Retarded growth and development, Genital hypoplasia, and Ear anomalies and deafness, most often caused by a genetic mutation in the CHD7 gene. Two features were then added: semicircular canal anomalies and arhinencephaly/olfactory bulb agenesis, with classification of typical, partial, or atypical forms on the basis of major and minor clinical criteria. The detection rate of a pathogenic variant in the CHD7 gene varies from 67% to 90%. To try to have an overview of this heterogenous clinical condition and specify a genotype-phenotype relation, we conducted a national study of phenotype and genotype in 119 patients with CS. Selected clinical diagnostic criteria were from Verloes (2005), updated by Blake & Prasad (). Besides obtaining a detailed clinical description, when possible, patients underwent a full ophthalmologic examination, audiometry, temporal bone CT scan, gonadotropin analysis, and olfactory-bulb MRI. All patients underwent CHD7 sequencing and MLPA analysis. We found a pathogenic CHD7 variant in 83% of typical CS cases and 58% of atypical cases. Pathogenic variants in the CHD7 gene were classified by the expected impact on the protein. In all, 90% of patients had a typical form of CS and 10% an atypical form. The most frequent features were deafness/semicircular canal hypoplasia (94%), pituitary defect/hypogonadism (89%), external ear anomalies (87%), square-shaped face (81%), and arhinencephaly/anosmia (80%). Coloboma (73%), heart defects (65%), and choanal atresia (43%) were less frequent.
Subject(s)
CHARGE Syndrome/diagnosis , CHARGE Syndrome/genetics , Genetic Association Studies , Genotype , Phenotype , Abnormalities, Multiple/diagnosis , Abnormalities, Multiple/genetics , Adolescent , Adult , Alleles , Amino Acid Substitution , Central Nervous System/abnormalities , Child , Child, Preschool , Cohort Studies , Cranial Nerves/abnormalities , DNA Helicases/genetics , DNA-Binding Proteins/genetics , Female , France , Genetic Testing , Humans , Infant , Male , Molecular Diagnostic Techniques , Young AdultABSTRACT
BACKGROUND: Inherited cardiac conduction disease is a rare bradyarrhythmia associated with mutations in various genes that affect action potential propagation. It is often characterized by isolated conduction disturbance of the His-Purkinje system, but it is rarely described as a syndromic form. OBJECTIVES: The authors sought to identify the genetic defect in families with a novel bradyarrhythmia syndrome associated with bone malformation. METHODS: The authors genetically screened 15 European cases with genotype-negative de novo atrioventricular (AV) block and their parents by trio whole-exome sequencing, plus 31 Japanese cases with genotype-negative familial AV block or sick sinus syndrome by targeted exon sequencing of 457 susceptibility genes. Functional consequences of the mutation were evaluated using an in vitro cell expression system and in vivo knockout mice. RESULTS: The authors identified a connexin-45 (Cx45) mutation (p.R75H) in 2 unrelated families (a de novo French case and a 3-generation Japanese family) who presented with progressive AV block, which resulted in atrial standstill without ventricular conduction abnormalities. Affected individuals shared a common extracardiac phenotype: a brachyfacial pattern, finger deformity, and dental dysplasia. Mutant Cx45 expressed in Neuro-2a cells showed normal hemichannel assembly and plaque formation. However, Lucifer yellow dye transfer and gap junction conductance between cell pairs were severely impaired, which suggested that mutant Cx45 impedes gap junction communication in a dominant-negative manner. Tamoxifen-induced, cardiac-specific Cx45 knockout mice showed sinus node dysfunction and atrial arrhythmia, recapitulating the intra-atrial disturbance. CONCLUSIONS: Altogether, the authors showed that Cx45 mutant p.R75H is responsible for a novel disease entity of progressive atrial conduction system defects associated with craniofacial and dentodigital malformation.
Subject(s)
Atrioventricular Block/etiology , Connexins/genetics , DNA/genetics , Dentofacial Deformities/complications , Mutation , Adolescent , Adult , Animals , Atrioventricular Block/genetics , Atrioventricular Block/physiopathology , Child , Child, Preschool , Connexins/metabolism , DNA Mutational Analysis , Dentofacial Deformities/genetics , Dentofacial Deformities/metabolism , Disease Models, Animal , Disease Progression , Electrocardiography , Female , Humans , Male , Mice , Mice, Transgenic , Middle Aged , Pedigree , Phenotype , Young AdultABSTRACT
BACKGROUND: Most arteriovenous malformations (AVMs) are localized and occur sporadically. However, they also can be multifocal in autosomal-dominant disorders, such as hereditary hemorrhagic telangiectasia and capillary malformation (CM)-AVM. Previously, we identified RASA1 mutations in 50% of patients with CM-AVM. Herein we studied non-RASA1 patients to further elucidate the pathogenicity of CMs and AVMs. METHODS: We conducted a genome-wide linkage study on a CM-AVM family. Whole-exome sequencing was also performed on 9 unrelated CM-AVM families. We identified a candidate gene and screened it in a large series of patients. The influence of several missense variants on protein function was also studied in vitro. RESULTS: We found evidence for linkage in 2 loci. Whole-exome sequencing data unraveled 4 distinct damaging variants in EPHB4 in 5 families that cosegregated with CM-AVM. Overall, screening of EPHB4 detected 47 distinct mutations in 54 index patients: 27 led to a premature stop codon or splice-site alteration, suggesting loss of function. The other 20 are nonsynonymous variants that result in amino acid substitutions. In vitro expression of several mutations confirmed loss of function of EPHB4. The clinical features included multifocal CMs, telangiectasias, and AVMs. CONCLUSIONS: We found EPHB4 mutations in patients with multifocal CMs associated with AVMs. The phenotype, CM-AVM2, mimics RASA1-related CM-AVM1 and also hereditary hemorrhagic telangiectasia. RASA1-encoded p120RASGAP is a direct effector of EPHB4. Our data highlight the pathogenetic importance of this interaction and indicts EPHB4-RAS-ERK signaling pathway as a major cause for AVMs.
Subject(s)
Arteriovenous Malformations/diagnosis , Arteriovenous Malformations/genetics , Capillaries/abnormalities , Germ-Line Mutation/genetics , MAP Kinase Signaling System/physiology , Port-Wine Stain/diagnosis , Port-Wine Stain/genetics , Receptor, EphB4/genetics , p120 GTPase Activating Protein/genetics , Databases, Genetic , Female , Genome-Wide Association Study/methods , Humans , Male , PedigreeSubject(s)
Brain Diseases/genetics , Carrier Proteins/genetics , Epilepsy/genetics , Phenotype , Psychomotor Disorders/genetics , Sequence Deletion , Alleles , Brain/abnormalities , Brain Diseases/diagnosis , Child , Codon , Epilepsy/diagnosis , Genotype , Humans , Magnetic Resonance Imaging , Male , Psychomotor Disorders/diagnosis , Severity of Illness IndexABSTRACT
Degradation of proteins by the ubiquitin-proteasome system (UPS) is an essential biological process in the development of eukaryotic organisms. Dysregulation of this mechanism leads to numerous human neurodegenerative or neurodevelopmental disorders. Through a multi-center collaboration, we identified six de novo genomic deletions and four de novo point mutations involving PSMD12, encoding the non-ATPase subunit PSMD12 (aka RPN5) of the 19S regulator of 26S proteasome complex, in unrelated individuals with intellectual disability, congenital malformations, ophthalmologic anomalies, feeding difficulties, deafness, and subtle dysmorphic facial features. We observed reduced PSMD12 levels and an accumulation of ubiquitinated proteins without any impairment of proteasome catalytic activity. Our PSMD12 loss-of-function zebrafish CRISPR/Cas9 model exhibited microcephaly, decreased convolution of the renal tubules, and abnormal craniofacial morphology. Our data support the biological importance of PSMD12 as a scaffolding subunit in proteasome function during development and neurogenesis in particular; they enable the definition of a neurodevelopmental disorder due to PSMD12 variants, expanding the phenotypic spectrum of UPS-dependent disorders.
Subject(s)
Neurodevelopmental Disorders/genetics , Proteasome Endopeptidase Complex/genetics , Adolescent , Animals , Child , Child, Preschool , DNA Copy Number Variations , Disease Models, Animal , Down-Regulation , Female , Gene Deletion , Humans , Infant , Intellectual Disability/genetics , Male , Microcephaly/genetics , Polymorphism, Single Nucleotide , Zebrafish/geneticsABSTRACT
Defects in OFD1 underlie the clinically complex ciliopathy, Oral-Facial-Digital syndrome Type I (OFD Type I). Our understanding of the molecular, cellular and clinical consequences of impaired OFD1 originates from its characterised roles at the centrosome/basal body/cilia network. Nonetheless, the first described OFD1 interactors were components of the TIP60 histone acetyltransferase complex. We find that OFD1 can also localise to chromatin and its reduced expression is associated with mis-localization of TIP60 in patient-derived cell lines. TIP60 plays important roles in controlling DNA repair. OFD Type I cells exhibit reduced histone acetylation and altered chromatin dynamics in response to DNA double strand breaks (DSBs). Furthermore, reduced OFD1 impaired DSB repair via homologous recombination repair (HRR). OFD1 loss also adversely impacted upon the DSB-induced G2-M checkpoint, inducing a hypersensitive and prolonged arrest. Our findings show that OFD Type I patient cells have pronounced defects in the DSB-induced histone modification, chromatin remodelling and DSB-repair via HRR; effectively phenocopying loss of TIP60. These data extend our knowledge of the molecular and cellular consequences of impaired OFD1, demonstrating that loss of OFD1 can negatively impact upon important nuclear events; chromatin plasticity and DNA repair.
Subject(s)
Chromatin/metabolism , Cilia/pathology , DNA Repair/genetics , Orofaciodigital Syndromes/genetics , Orofaciodigital Syndromes/pathology , Proteins/metabolism , Recombination, Genetic/genetics , Acetylation , Cell Cycle Checkpoints/genetics , Cell Nucleus/genetics , Cell Nucleus/metabolism , Cells, Cultured , Chromatin/genetics , Cilia/enzymology , DNA Breaks, Double-Stranded , Fibroblasts , HeLa Cells , Histones/genetics , Histones/metabolism , Humans , Orofaciodigital Syndromes/metabolism , Proteins/antagonists & inhibitors , Proteins/genetics , RNA, Small Interfering/geneticsABSTRACT
Rubinstein-Taybi syndrome (RSTS) is a developmental disorder characterized by a typical face and distal limbs abnormalities, intellectual disability, and a vast number of other features. Two genes are known to cause RSTS, CREBBP in 60% and EP300 in 8-10% of clinically diagnosed cases. Both paralogs act in chromatin remodeling and encode for transcriptional co-activators interacting with >400 proteins. Up to now 26 individuals with an EP300 mutation have been published. Here, we describe the phenotype and genotype of 42 unpublished RSTS patients carrying EP300 mutations and intragenic deletions and offer an update on another 10 patients. We compare the data to 308 individuals with CREBBP mutations. We demonstrate that EP300 mutations cause a phenotype that typically resembles the classical RSTS phenotype due to CREBBP mutations to a great extent, although most facial signs are less marked with the exception of a low-hanging columella. The limb anomalies are more similar to those in CREBBP mutated individuals except for angulation of thumbs and halluces which is very uncommon in EP300 mutated individuals. The intellectual disability is variable but typically less marked whereas the microcephaly is more common. All types of mutations occur but truncating mutations and small rearrangements are most common (86%). Missense mutations in the HAT domain are associated with a classical RSTS phenotype but otherwise no genotype-phenotype correlation is detected. Pre-eclampsia occurs in 12/52 mothers of EP300 mutated individuals versus in 2/59 mothers of CREBBP mutated individuals, making pregnancy with an EP300 mutated fetus the strongest known predictor for pre-eclampsia. © 2016 Wiley Periodicals, Inc.
Subject(s)
CREB-Binding Protein/genetics , E1A-Associated p300 Protein/genetics , Pre-Eclampsia/genetics , Rubinstein-Taybi Syndrome/genetics , Adult , Chromatin Assembly and Disassembly/genetics , Female , Genetic Association Studies , Genetic Predisposition to Disease , Genotype , Humans , Male , Middle Aged , Mutation, Missense/genetics , Pre-Eclampsia/physiopathology , Pregnancy , Rubinstein-Taybi Syndrome/pathology , Sequence DeletionABSTRACT
KBG syndrome, due to ANKRD11 alteration is characterized by developmental delay, short stature, dysmorphic facial features, and skeletal anomalies. We report a clinical and molecular study of 39 patients affected by KBG syndrome. Among them, 19 were diagnosed after the detection of a 16q24.3 deletion encompassing the ANKRD11 gene by array CGH. In the 20 remaining patients, the clinical suspicion was confirmed by the identification of an ANKRD11 mutation by direct sequencing. We present arguments to modulate the previously reported diagnostic criteria. Macrodontia should no longer be considered a mandatory feature. KBG syndrome is compatible with autonomous life in adulthood. Autism is less frequent than previously reported. We also describe new clinical findings with a potential impact on the follow-up of patients, such as precocious puberty and a case of malignancy. Most deletions remove the 5'end or the entire coding region but never extend toward 16q telomere suggesting that distal 16q deletion could be lethal. Although ANKRD11 appears to be a major gene associated with intellectual disability, KBG syndrome remains under-diagnosed. NGS-based approaches for sequencing will improve the detection of point mutations in this gene. Broad knowledge of the clinical phenotype is essential for a correct interpretation of the molecular results. © 2016 Wiley Periodicals, Inc.
Subject(s)
Abnormalities, Multiple/diagnosis , Abnormalities, Multiple/genetics , Bone Diseases, Developmental/diagnosis , Bone Diseases, Developmental/genetics , Genetic Association Studies , Intellectual Disability/diagnosis , Intellectual Disability/genetics , Mutation , Repressor Proteins/genetics , Tooth Abnormalities/diagnosis , Tooth Abnormalities/genetics , Adolescent , Adult , Aged , Alleles , Amino Acid Substitution , Child , Child, Preschool , Chromosome Deletion , Chromosomes, Human, Pair 16 , Comparative Genomic Hybridization , Facies , Female , Humans , Infant , Male , Middle Aged , Phenotype , Retrospective Studies , Young AdultABSTRACT
Due to the lack of a valid approach in the design of electrochemical interfaces modified with enzymes for efficient catalysis, many oxidoreductases are still not addressed by electrochemistry. We report in this work an in-depth study of the interactions between two different bilirubin oxidases, (from the fungus Myrothecium verrucaria and from the bacterium Bacillus pumilus), catalysts of oxygen reduction, and carbon nanotubes bearing various surface charges (pristine, carboxylic-, and pyrene-methylamine-functionalized). The surface charges and dipole moment of the enzymes as well as the surface state of the nanomaterials are characterized as a function of pH. An original electrochemical approach allows determination of the best interface for direct or mediated electron transfer processes as a function of enzyme, nanomaterial type, and adsorption conditions. We correlate these experimental results to theoric voltammetric curves. Such an integrative study suggests strategies for designing efficient bioelectrochemical interfaces toward the elaboration of biodevices such as enzymatic fuel cells for sustainable electricity production.
ABSTRACT
BACKGROUND: Cascade carrier testing within cystic fibrosis (CF) affected families offers relatives of CF patients the opportunity to know their status regarding the mutation that segregates within their family, and thus to make informed reproductive choices. As an Australian study has recently shown that this test seemed underused, we searched to assess uptake of this test in a European area where CF is common, and to report its public health implications. METHODS: This study relied on 40 CF-affected families from western Brittany, France. Investigations included drawing of family trees and registration of carrier tests performed in those families. RESULTS: Of the 459 relatives eligible for testing, 185 were tested, leading to an adjusted uptake rate of testing of 40.7% (95% CI: [34.1%; 47.3%]). The main predictors for having testing were being female (p=0.031) and having a high prior risk (p<0.001). Planning a pregnancy or expecting a child (reported in at least 38.4% of tested relatives) also appeared critical in choosing to be tested. Overall, carrier testing allowed to reassure more than 1/4 of the relatives and to detect five new 1-in-4 at-risk couples who then requested prenatal diagnosis. CONCLUSIONS: This observational study assesses, for first time in Europe, uptake of CF cascade carrier testing within CF families, which is a critical tool to reassure non-carriers and to detect early new at-risk couples.
Subject(s)
Cystic Fibrosis , Genetic Counseling/psychology , Adult , Choice Behavior , Cystic Fibrosis/diagnosis , Cystic Fibrosis/epidemiology , Cystic Fibrosis/genetics , Cystic Fibrosis/psychology , Family Health , Female , France/epidemiology , Genetic Carrier Screening/methods , Genetic Carrier Screening/statistics & numerical data , Humans , Male , Pregnancy , Prenatal Diagnosis/methods , Prenatal Diagnosis/psychology , Prenatal Diagnosis/statistics & numerical data , Reproductive Health , Risk Assessment/methodsABSTRACT
A rare syndromic form of intellectual disability with impaired speech was recently found associated with mutations in CHAMP1 (chromosome alignment-maintaining phosphoprotein 1), the protein product of which is directly involved in microtubule-kinetochore attachment. Through whole-exome sequencing in six unrelated nonconsanguineous families having a sporadic case of intellectual disability, we identified six novel de novo truncating mutations in CHAMP1: c.1880C>G p.(Ser627*), c.1489C>T; p.(Arg497*), c.1876_1877delAG; p.(Ser626Leufs*4), c.1043G>A; p.(Trp348*), c.1002G>A; p.(Trp334*), and c.958_959delCC; p.(Pro320*). Our clinical observations confirm the phenotypic homogeneity of the syndrome, which represents therefore a distinct clinical entity. Besides, our functional studies show that CHAMP1 protein variants are delocalized from chromatin and are unable to bind to two of its direct partners, POGZ and HP1. These data suggest a pathogenic mechanism of the CHAMP1-associated intellectual disability syndrome mediated by direct interacting partners of CHAMP1, several of which are involved in chromo/kinetochore-related disorders.
Subject(s)
Chromosomal Proteins, Non-Histone/genetics , Intellectual Disability/genetics , Phosphoproteins/genetics , Sequence Deletion , Alleles , Child , Child, Preschool , Exome , Facies , Female , High-Throughput Nucleotide Sequencing , Humans , Intellectual Disability/diagnosis , Male , Phenotype , SyndromeABSTRACT
Hypophosphatasia (HPP) is a rare inherited skeletal dysplasia due to loss of function mutations in the ALPL gene. The disease is subject to an extremely high clinical heterogeneity ranging from a perinatal lethal form to odontohypophosphatasia affecting only teeth. Up to now genetic diagnosis of HPP is performed by sequencing the ALPL gene by Sanger methodology. Osteogenesis imperfecta (OI) and campomelic dysplasia (CD) are the main differential diagnoses of severe HPP, so that in case of negative result for ALPL mutations, OI and CD genes had often to be analyzed, lengthening the time before diagnosis. We report here our 18-month experience in testing 46 patients for HPP and differential diagnosis by targeted NGS and show that this strategy is efficient and useful. We used an array including ALPL gene, genes of differential diagnosis COL1A1 and COL1A2 that represent 90% of OI cases, SOX9, responsible for CD, and 8 potentially modifier genes of HPP. Seventeen patients were found to carry a mutation in one of these genes. Among them, only 10 out of 15 cases referred for HPP carried a mutation in ALPL and 5 carried a mutation in COL1A1 or COL1A2. Interestingly, three of these patients were adults with fractures and/or low BMD. Our results indicate that HPP and OI may be easily misdiagnosed in the prenatal stage but also in adults with mild symptoms for these diseases.
Subject(s)
Hypophosphatasia/diagnosis , Hypophosphatasia/genetics , Adult , Aged , Campomelic Dysplasia/diagnosis , Child, Preschool , Diagnosis, Differential , Female , Fetus , High-Throughput Nucleotide Sequencing , Humans , Hypophosphatasia/physiopathology , Infant , Male , Middle Aged , Mutation , Oligonucleotide Array Sequence Analysis , Osteogenesis Imperfecta/diagnosis , Tooth Demineralization/congenital , Tooth Demineralization/physiopathologyABSTRACT
Heterogeneous nitrate photolysis is the trigger for many chemical processes occurring in the polar boundary layer and is widely believed to occur in a quasi-liquid layer (QLL) at the surface of ice. The dipole-forbidden character of the electronic transition relevant to boundary layer atmospheric chemistry and the small photolysis/photoproduct yields in ice (and in water) may confer a significant enhancement and interfacial specificity to this important photochemical reaction at the surface of ice. Using amorphous solid water films at cryogenic temperatures as models for the disordered interstitial air-ice interface within the snowpack suppresses the diffusive uptake kinetics, thereby prolonging the residence time of nitrate anions at the surface of ice. This approach allows their slow heterogeneous photolysis kinetics to be studied, providing the first direct evidence that nitrates adsorbed onto the first molecular layer at the surface of ice are photolyzed more effectively than those dissolved within the bulk. Vibrational spectroscopy allows the â¼3-fold enhancement in photolysis rates to be correlated with the nitrates' distorted intramolecular geometry, thereby hinting at the role played by the greater chemical heterogeneity in their solvation environment at the surface of ice than that in the bulk. A simple 1D kinetic model suggests (1) that a 3(6)-fold enhancement in photolysis rate for nitrates adsorbed onto the ice surface could increase the photochemical NO2 emissions from a 5(8) nm thick photochemically active interfacial layer by 30(60)%, and (2) that 25(40)% of the NO2 photochemical emissions to the snowpack interstitial air are released from the topmost molecularly thin surface layer on ice. These findings may provide a new paradigm for heterogeneous (photo)chemistry at temperatures below those required for a QLL to form at the ice surface.
ABSTRACT
CONTEXT: Mutations in CHD7, a gene previously implicated in CHARGE (coloboma, heart defect, choanal atresia, retardation of growth and/or development, genital hypoplasia, ear anomalies) syndrome, have been reported in patients presenting with Kallmann syndrome (KS) or congenital hypogonadotropic hypogonadism (CHH). Most mutations causing CHARGE syndrome result in premature stop codons and occur de novo, but the proportion of truncating vs nontruncating mutations in KS and CHH patients is still unknown. OBJECTIVE: The objective of the study was to determine the nature, prevalence, mode of transmission, and clinical spectrum of CHD7 mutations in a large series of patients. DESIGN: We studied 209 KS and 94 CHH patients. These patients had not been diagnosed with CHARGE syndrome according to the current criteria. We searched for mutations in 16 KS and CHH genes including CHD7. RESULTS: We found presumably pathogenic mutations in CHD7 in 24 KS patients but not in CHH patients. Nontruncating mutations (16 missense and a two-codon duplication) were more prevalent than truncating mutations (three nonsense, three frame shift, and a splice site), which contrasts with patients presenting with typical CHARGE syndrome. Thus, the clinical spectrum associated with CHD7 mutations may be partly explained by genotype/phenotype correlations. Eight patients also had congenital deafness and one had a cleft lip/palate, whereas six had both. For 10 patients, the presence of diverse features of the CHARGE spectrum in at least one relative argues against a de novo appearance of the missense mutation, and this was confirmed by genetic analysis in five families. CONCLUSION: Considering the large prevalence and clinical spectrum of CHD7 mutations, it will be particularly relevant to genetic counseling to search for mutations in this gene in KS patients seeking fertility treatment, especially if KS is associated with deafness and cleft lip/palate.
Subject(s)
CHARGE Syndrome/epidemiology , CHARGE Syndrome/genetics , DNA Helicases/genetics , DNA-Binding Proteins/genetics , Kallmann Syndrome/epidemiology , Kallmann Syndrome/genetics , Adolescent , Adult , Child , Child, Preschool , Family Health , Female , Frameshift Mutation , Genotype , Heterozygote , Humans , Male , Middle Aged , Mutation, Missense , Pedigree , Phenotype , Prevalence , Young AdultABSTRACT
BACKGROUND: Oral-facial-digital type 1 syndrome (OFD1; OMIM 311200) belongs to the expanding group of disorders ascribed to ciliary dysfunction. With the aim of contributing to the understanding of the role of primary cilia in the central nervous system (CNS), we performed a thorough characterization of CNS involvement observed in this disorder. METHODS: A cohort of 117 molecularly diagnosed OFD type I patients was screened for the presence of neurological symptoms and/or cognitive/behavioral abnormalities on the basis of the available information supplied by the collaborating clinicians. Seventy-one cases showing CNS involvement were further investigated through neuroimaging studies and neuropsychological testing. RESULTS: Seventeen patients were molecularly diagnosed in the course of this study and five of these represent new mutations never reported before. Among patients displaying neurological symptoms and/or cognitive/behavioral abnormalities, we identified brain structural anomalies in 88.7%, cognitive impairment in 68%, and associated neurological disorders and signs in 53% of cases. The most frequently observed brain structural anomalies included agenesis of the corpus callosum and neuronal migration/organisation disorders as well as intracerebral cysts, porencephaly and cerebellar malformations. CONCLUSIONS: Our results support recent published findings indicating that CNS involvement in this condition is found in more than 60% of cases. Our findings correlate well with the kind of brain developmental anomalies described in other ciliopathies. Interestingly, we also described specific neuropsychological aspects such as reduced ability in processing verbal information, slow thought process, difficulties in attention and concentration, and notably, long-term memory deficits which may indicate a specific role of OFD1 and/or primary cilia in higher brain functions.
Subject(s)
Central Nervous System Diseases/physiopathology , Orofaciodigital Syndromes/physiopathology , Central Nervous System Diseases/genetics , Central Nervous System Diseases/psychology , Cohort Studies , Female , Humans , Magnetic Resonance Imaging , Mutation , Neuropsychological Tests , Orofaciodigital Syndromes/genetics , Orofaciodigital Syndromes/psychologyABSTRACT
The genetic causes of malformations of cortical development (MCD) remain largely unknown. Here we report the discovery of multiple pathogenic missense mutations in TUBG1, DYNC1H1 and KIF2A, as well as a single germline mosaic mutation in KIF5C, in subjects with MCD. We found a frequent recurrence of mutations in DYNC1H1, implying that this gene is a major locus for unexplained MCD. We further show that the mutations in KIF5C, KIF2A and DYNC1H1 affect ATP hydrolysis, productive protein folding and microtubule binding, respectively. In addition, we show that suppression of mouse Tubg1 expression in vivo interferes with proper neuronal migration, whereas expression of altered γ-tubulin proteins in Saccharomyces cerevisiae disrupts normal microtubule behavior. Our data reinforce the importance of centrosomal and microtubule-related proteins in cortical development and strongly suggest that microtubule-dependent mitotic and postmitotic processes are major contributors to the pathogenesis of MCD.