RESUMO
While it is widely thought that de novo mutations (DNMs) occur randomly, we previously showed that some DNMs are enriched because they are positively selected in the testes of aging men. These "selfish" mutations cause disorders with a shared presentation of features, including exclusive paternal origin, significant increase of the father's age, and high apparent germline mutation rate. To date, all known selfish mutations cluster within the components of the RTK-RAS-MAPK signaling pathway, a critical modulator of testicular homeostasis. Here, we demonstrate the selfish nature of the SMAD4 DNMs causing Myhre syndrome (MYHRS). By analyzing 16 informative trios, we show that MYHRS-causing DNMs originated on the paternally derived allele in all cases. We document a statistically significant epidemiological paternal age effect of 6.3 years excess for fathers of MYHRS probands. We developed an ultra-sensitive assay to quantify spontaneous MYHRS-causing SMAD4 variants in sperm and show that pathogenic variants at codon 500 are found at elevated level in sperm of most men and exhibit a strong positive correlation with donor's age, indicative of a high apparent germline mutation rate. Finally, we performed in vitro assays to validate the peculiar functional behavior of the clonally selected DNMs and explored the basis of the pathophysiology of the different SMAD4 sperm-enriched variants. Taken together, these data provide compelling evidence that SMAD4, a gene operating outside the canonical RAS-MAPK signaling pathway, is associated with selfish spermatogonial selection and raises the possibility that other genes/pathways are under positive selection in the aging human testis.
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Helsmoortel-Van der Aa syndrome (HVDAS) is a neurodevelopmental condition associated with intellectual disability/developmental delay, autism spectrum disorder, and multiple medical comorbidities. HVDAS is caused by mutations in activity-dependent neuroprotective protein (ADNP). A recent study identified genome-wide DNA methylation changes in 22 individuals with HVDAS, adding to the group of neurodevelopmental disorders with an epigenetic signature. This methylation signature segregated those with HVDAS into two groups based on the location of the mutations. Here, we conducted an independent study on 24 individuals with HVDAS and replicated the existence of the two mutation-dependent episignatures. To probe whether the two distinct episignatures correlate with clinical outcomes, we used deep behavioral and neurobiological data from two prospective cohorts of individuals with a genetic diagnosis of HVDAS. We found limited phenotypic differences between the two HVDAS-affected groups and no evidence that individuals with more widespread methylation changes are more severely affected. Moreover, in spite of the methylation changes, we observed no profound alterations in the blood transcriptome of individuals with HVDAS. Our data warrant caution in harnessing methylation signatures in HVDAS as a tool for clinical stratification, at least with regard to behavioral phenotypes.
Assuntos
Transtorno do Espectro Autista/genética , Proteínas de Homeodomínio/genética , Deficiência Intelectual/genética , Proteínas do Tecido Nervoso/genética , Transtornos do Neurodesenvolvimento/genética , Transtorno do Espectro Autista/patologia , Criança , Metilação de DNA/genética , Deficiências do Desenvolvimento/genética , Deficiências do Desenvolvimento/patologia , Epigênese Genética/genética , Feminino , Humanos , Deficiência Intelectual/patologia , Masculino , Mutação/genética , Transtornos do Neurodesenvolvimento/patologia , Fenótipo , Transcriptoma/genéticaRESUMO
Two adult siblings born to first-cousin parents presented a clinical phenotype reminiscent of Rothmund-Thomson syndrome (RTS), implying fragile hair, absent eyelashes/eyebrows, bilateral cataracts, mottled pigmentation, dental decay, hypogonadism, and osteoporosis. As the clinical suspicion was not supported by the sequencing of RECQL4, the RTS2-causative gene, whole exome sequencing was applied and disclosed the homozygous variants c.83G>A (p.Gly28Asp) and c.2624A>C (p.Glu875Ala) in the nucleoporin 98 (NUP98) gene. Though both variants affect highly conserved amino acids, the c.83G>A looked more intriguing due to its higher pathogenicity score and location of the replaced amino acid between phenylalanine-glycine (FG) repeats within the first NUP98 intrinsically disordered region. Molecular modeling studies of the mutated NUP98 FG domain evidenced a dispersion of the intramolecular cohesion elements and a more elongated conformational state compared to the wild type. This different dynamic behavior may affect the NUP98 functions as the minor plasticity of the mutated FG domain undermines its role as a multi-docking station for RNA and proteins, and the impaired folding can lead to the weakening or the loss of specific interactions. The clinical overlap of NUP98-mutated and RTS2/RTS1 patients, accounted by converging dysregulated gene networks, supports this first-described constitutional NUP98 disorder, expanding the well-known role of NUP98 in cancer.
Assuntos
Mutação em Linhagem Germinativa , Complexo de Proteínas Formadoras de Poros Nucleares , Síndrome de Rothmund-Thomson , Humanos , Complexo de Proteínas Formadoras de Poros Nucleares/química , Complexo de Proteínas Formadoras de Poros Nucleares/genética , Síndrome de Rothmund-Thomson/genética , Irmãos , Masculino , Feminino , Conformação ProteicaRESUMO
PURPOSE: This study aimed to describe a multisystemic disorder featuring cardiovascular, facial, musculoskeletal, and cutaneous anomalies caused by heterozygous loss-of-function variants in TAB2. METHODS: Affected individuals were analyzed by next-generation technologies and genomic array. The presumed loss-of-function effect of identified variants was assessed by luciferase assay in cells transiently expressing TAB2 deleterious alleles. In available patients' fibroblasts, variant pathogenicity was further explored by immunoblot and osteoblast differentiation assays. The transcriptomic profile of fibroblasts was investigated by RNA sequencing. RESULTS: A total of 11 individuals from 8 families were heterozygotes for a novel TAB2 variant. In total, 7 variants were predicted to be null alleles and 1 was a missense change. An additional subject was heterozygous for a 52 kb microdeletion involving TAB2 exons 1 to 3. Luciferase assay indicated a decreased transcriptional activation mediated by NF-κB signaling for all point variants. Immunoblot analysis showed a reduction of TAK1 phosphorylation while osteoblast differentiation was impaired. Transcriptomic analysis identified deregulation of multiple pleiotropic pathways, such as TGFß-, Ras-MAPK-, and Wnt-signaling networks. CONCLUSION: Our data defined a novel disorder associated with loss-of-function or, more rarely, hypomorphic alleles in a restricted linker region of TAB2. The pleiotropic manifestations in this disorder partly recapitulate the 6q25.1 (TAB2) microdeletion syndrome and deserve the definition of cardio-facial-cutaneous-articular syndrome.
Assuntos
Proteínas Adaptadoras de Transdução de Sinal , NF-kappa B , Proteínas Adaptadoras de Transdução de Sinal/genética , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Éxons/genética , Humanos , NF-kappa B/genética , NF-kappa B/metabolismo , Fosforilação , Transdução de SinaisRESUMO
The vast majority of reported (likely) pathogenic missense variants in the genes coding for the fibrillar collagens leads to the substitution of one of the obligatory glycine residues in the Gly-Xaa-Yaa repeat sequence of the triple helical domain. Their phenotypic consequences and deleterious effects have been well-documented. However, with increasing access to molecular diagnostic testing based on next-generation sequencing techniques, such as sequencing of multi-gene panels and whole-exome sequencing, non-glycine substitutions are more frequently identified in individuals suspected to have a heritable collagen disorder, but their pathogenic effect is often difficult to predict.Some specific non-glycine substitutions in the proα1(I)- (p.(Arg312Cys)) and proα1(III)- (glutamic acid to lysine at different positions) collagen chain have been identified in a number of individuals presenting a phenotype showing features of both classical and vascular Ehlers-Danlos syndrome. The number of reported individuals with these defects is currently very low, and several of these non-glycine substitutions had initially been categorised as variants of unknown significance (VUS), complicating early diagnosis, accurate counselling, management guidelines, and correct classification. This collaborative study reports on the phenotype of 22 and 7 individuals harbouring these rare variants in COL1A1 and COL3A1, respectively, expanding our knowledge on clinical presentation, phenotypic variability, and natural history, and informing on the risk for potentially life-threatening events, such as vascular, gastro-intestinal, and pregnancy-related complications.
Assuntos
Cadeia alfa 1 do Colágeno Tipo I , Síndrome de Ehlers-Danlos , Colágeno , Colágeno Tipo III/genética , Síndrome de Ehlers-Danlos/complicações , Síndrome de Ehlers-Danlos/diagnóstico , Síndrome de Ehlers-Danlos/genética , Humanos , Mutação , FenótipoRESUMO
Biallelic pathogenic variants in POC1A result in SOFT (Short-stature, Onychodysplasia, Facial-dysmorphism, and hypoTrichosis) and variant POC1A-related (vPOC1A) syndromes. The latter, nowadays described in only two unrelated subjects, is associated with a restricted spectrum of variants falling in exon 10, which is naturally skipped in a specific POC1A mRNA. The synthesis of an amount of a POC1A isoform from this transcript in individuals with vPOC1A syndrome has been believed as the likely explanation for such a genotype-phenotype correlation. Here, we illustrate the clinical and molecular findings in a woman who resulted to be compound heterozygous for a recurrent frameshift variant in exon 10 and a novel variant in exon 9 of POC1A. Phenotypic characteristics of this woman included severe hyperinsulinemic dyslipidemia, acanthosis nigricans, moderate growth restriction, and dysmorphisms. These manifestations overlap the clinical features of the two previously published individuals with vPOC1A syndrome. RT-PCR analysis on peripheral blood and subsequent sequencing of the obtained amplicons demonstrated a variety of POC1A alternative transcripts that resulted to be expressed in the proband, in the healthy mother, and in controls. We illustrate the possible consequences of the two POC1A identified variants in an attempt to explain pleiotropy in vPOC1A syndrome.
Assuntos
Proteínas de Ciclo Celular/genética , Hiperinsulinismo Congênito/genética , Proteínas do Citoesqueleto/genética , Dislipidemias/genética , Acantose Nigricans/genética , Adulto , Idade de Início , Proteínas de Ciclo Celular/deficiência , Simulação por Computador , Hiperinsulinismo Congênito/tratamento farmacológico , Proteínas do Citoesqueleto/deficiência , DNA Complementar/genética , Dislipidemias/tratamento farmacológico , Éxons/genética , Ácidos Graxos Insaturados/uso terapêutico , Feminino , Mutação da Fase de Leitura , Heterozigoto , Humanos , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Resistência à Insulina , Metformina/uso terapêutico , Pessoa de Meia-Idade , Linhagem , Fenótipo , Plasmaferese , Isoformas de Proteínas/genética , Síndrome , Transcrição GênicaRESUMO
Koolen-de Vries syndrome (KdVS, MIM#610443) is a rare malformation condition mainly characterized by cognitive impairment in association with craniofacial and visceral anomalies. The core phenotype is caused by mutations in the chromatin remodeler KANSL1 (MSL1V1, KIAA1267, KAT8 Regulatory NSL Complex Subunit 1, MIM#612452), which maps to 17q21.31 critical genomic region (Koolen et al., Nature Genetics 2012;44:639-641). Considering its molecular basis, KdVS is included in the group of Developmental Disorders of Chromatin Remodeling (DDCRs), also termed chromatinopathies. We describe the first KdVS patient of Southern India ethnicity, harboring the typical de novo 17q21.31 microdeletion, including KANSL1. Observed facial features and congenital anomalies are in line with the already reported KdVS phenotype, suggesting that phenotypic features are consistent across different ethnicities.
Assuntos
Anormalidades Múltiplas/etnologia , Deficiência Intelectual/etnologia , Proteínas Nucleares/genética , Anormalidades Múltiplas/genética , Adulto , Envelhecimento , Deleção Cromossômica , Cromossomos Humanos Par 17/genética , Cromossomos Humanos Par 17/ultraestrutura , Etnicidade/genética , Face/anormalidades , Feminino , Comunicação Interatrial/genética , Comunicação Interatrial/cirurgia , Humanos , Índia , Recém-Nascido , Recém-Nascido Prematuro , Doenças do Prematuro/genética , Deficiência Intelectual/genética , Má Oclusão Classe III de Angle/genética , Fenótipo , Deleção de SequênciaRESUMO
We describe the second patient with the de novo p.Arg377Trp variant in ACTL6A (Actin-like 6A) (MIM#604958) and a phenotype reminiscent a disorder of the BRG1-associated factor (BAF) complex, including dysmorphic facies and acral malformations. So far, only three patients with ACTL6A variants and neurodevelopmental delay have been reported but the specific p.Arg377Trp mutation seems to correlate with a distinctive phenotype well-fitting a BAFopathy, which lacks in individuals carrying different mutations. This could suggest an emergent genotype-phenotype correlation among the ACTL6A-related phenotype.
Assuntos
Anormalidades Múltiplas/genética , Actinas/genética , Proteínas Cromossômicas não Histona/genética , Proteínas de Ligação a DNA/genética , Deformidades Congênitas da Mão/genética , Transtornos do Neurodesenvolvimento/genética , Anormalidades Múltiplas/patologia , Criança , Deformidades Congênitas da Mão/patologia , Humanos , Masculino , Micrognatismo/patologia , Transtornos do Neurodesenvolvimento/patologiaRESUMO
The 2017 classification of Ehlers-Danlos syndromes (EDS) identifies three types associated with causative variants in COL1A1/COL1A2 and distinct from osteogenesis imperfecta (OI). Previously, patients have been described with variable features of both disorders, and causative variants in COL1A1/COL1A2; but this phenotype has not been included in the current classification. Here, we expand and re-define this OI/EDS overlap as a missing EDS type. Twenty-one individuals from 13 families were reported, in whom COL1A1/COL1A2 variants were found after a suspicion of EDS. None of them could be classified as affected by OI or by any of the three recognized EDS variants associated with COL1A1/COL1A2. This phenotype is dominated by EDS-related features. OI-related features were limited to mildly reduced bone mass, occasional fractures and short stature. Eight COL1A1/COL1A2 variants were novel and five recurrent with a predominance of glycine substitutions affecting residues within the procollagen N-proteinase cleavage site of α1(I) and α2(I) procollagens. Selected variants were investigated by biochemical, ultrastructural and immunofluorescence studies. The pattern of observed changes in the dermis and in vitro for selected variants was more typical of EDS rather than OI. Our findings indicate the existence of a wider recognizable spectrum associated with COL1A1/COL1A2.
Assuntos
Colágeno Tipo I/genética , Doenças do Tecido Conjuntivo/classificação , Síndrome de Ehlers-Danlos/classificação , Variação Genética , Osteogênese Imperfeita/classificação , Adolescente , Adulto , Criança , Pré-Escolar , Colágeno Tipo I/ultraestrutura , Cadeia alfa 1 do Colágeno Tipo I , Tecido Conjuntivo/ultraestrutura , Doenças do Tecido Conjuntivo/genética , Demografia , Síndrome de Ehlers-Danlos/genética , Feminino , Heterozigoto , Humanos , Lactente , Masculino , Pessoa de Meia-Idade , Osteogênese Imperfeita/genética , Fenótipo , Adulto JovemRESUMO
A rare developmental delay (DD)/intellectual disability (ID) syndrome with craniofacial dysmorphisms and autistic features, termed White-Sutton syndrome (WHSUS, MIM#614787), has been recently described, identifying truncating mutations in the chromatin regulator POGZ (KIAA0461, MIM#614787). We describe a further WHSUS patient harboring a novel nonsense de novo POGZ variant, which afflicts a protein domain with transposase activity less frequently impacted by mutational events (DDE domain). This patient displays additional physical and behavioral features, these latter mimicking Smith-Magenis syndrome (SMS, MIM#182290). Considering sleep-wake cycle anomalies and abnormal behavior manifested by this boy, we reinforced the clinical resemblance between WHSUS and SMS, being both chromatinopathies. In addition, using the DeepGestalt technology, we identified a different facial overlap between WHSUS patients with mutations in the DDE domain (Group 1) and individuals harboring variants in other protein domains/regions (Group 2). This report further delineates the clinical and molecular repertoire of the POGZ-related phenotype, adding a novel patient with uncommon clinical and behavioral features and provides the first computer-aided facial study of WHSUS patients.
Assuntos
Deficiências do Desenvolvimento/genética , Deficiência Intelectual/genética , Síndrome de Smith-Magenis/genética , Transposases/genética , Pré-Escolar , Códon sem Sentido/genética , Anormalidades Craniofaciais/diagnóstico , Anormalidades Craniofaciais/diagnóstico por imagem , Anormalidades Craniofaciais/genética , Anormalidades Craniofaciais/fisiopatologia , Deficiências do Desenvolvimento/diagnóstico , Deficiências do Desenvolvimento/diagnóstico por imagem , Deficiências do Desenvolvimento/fisiopatologia , Exoma/genética , Feminino , Humanos , Deficiência Intelectual/diagnóstico , Deficiência Intelectual/diagnóstico por imagem , Deficiência Intelectual/fisiopatologia , Masculino , Mutação/genética , Fenótipo , Síndrome de Smith-Magenis/diagnóstico , Síndrome de Smith-Magenis/diagnóstico por imagem , Síndrome de Smith-Magenis/fisiopatologiaRESUMO
BACKGROUND: Cutaneous malignant melanoma (CMM) is one of the most common skin cancers worldwide. CMM pathogenesis involves genetic and environmental factors. Recent studies have led to the identification of new genes involved in CMM susceptibility: beyond CDKN2A and CDK4, BAP1, POT1, and MITF were recently identified as potential high-risk melanoma susceptibility genes. OBJECTIVE: This study is aimed to evaluate the genetic predisposition to CMM in patients from central Italy. METHODS: From 1998 to 2017, genetic testing was performed in 888 cases with multiple primary melanoma and/or familial melanoma. Genetic analyses included the sequencing CDKN2A, CDK4, BAP1, POT1, and MITF in 202 cases, and of only CDKN2A and CDK4 codon 24 in 686 patients. By the evaluation of the personal and familial history, patients were divided in two clinical categories: "low significance" and "high significance" cases. RESULTS: 128 patients (72% belonging to the "high significance" category, 28% belonging to the "low significance" category) were found to carry a DNA change defined as pathogenic, likely pathogenic, variant of unknown significance (VUS)-favoring pathogenic or VUS. CONCLUSIONS: It is important to verify the genetic predisposition in CMM patients for an early diagnosis of further melanomas and/or other tumors associated with the characterized genotype.
Assuntos
Predisposição Genética para Doença/genética , Melanoma/genética , Melanoma/metabolismo , Adulto , Idoso , Quinase 4 Dependente de Ciclina/genética , Inibidor p16 de Quinase Dependente de Ciclina/genética , Feminino , Humanos , Itália , Masculino , Fator de Transcrição Associado à Microftalmia/genética , Pessoa de Meia-Idade , Estudos Retrospectivos , Complexo Shelterina , Proteínas de Ligação a Telômeros/genética , Proteínas Supressoras de Tumor/genética , Ubiquitina Tiolesterase/genéticaRESUMO
Pancreatic cancer-melanoma syndrome (PCMS) is an inherited condition in which mutation carriers have an increased risk of malignant melanoma and/or pancreatic cancer. About 30% of PCMS cases carry mutations in CDKN2A. This gene encodes several protein isoforms, one of which, known as p16, regulates the cell-cycle by interacting with CDK4/CDK6 kinases and with several non-CDK proteins. Herein, we report on a novel CDKN2A germline in-frame deletion (c.52_57delACGGCC) found in an Italian family with PCMS. By segregation analysis, the c.52_57delACGGCC was proven to segregate in kindred with cutaneous melanoma (CM), in kindred with CM and pancreatic cancer, and in a single case presenting only with pancreatic cancer. In the literature, duplication mapping in the same genic region has been already reported at the germline level in several unrelated CM cases as a variant of unknown clinical significance. A computational approach for studying the effect of mutational changes over p16 protein structure showed that both the deletion and the duplication of the c.52_57 nucleotides result in protein misfolding and loss of interactors' binding. In conclusion, the present results argue that the quantitative alteration of nucleotides c.52_57 has a pathogenic role in p16 function and that the c.52_57delACGGCC is associated with PCMS.
Assuntos
Inibidor p16 de Quinase Dependente de Ciclina/genética , Mutação em Linhagem Germinativa , Melanoma/genética , Síndromes Neoplásicas Hereditárias/genética , Neoplasias Pancreáticas/genética , Inibidor p16 de Quinase Dependente de Ciclina/ultraestrutura , Feminino , Deleção de Genes , Humanos , Masculino , Melanoma/etiologia , Pessoa de Meia-Idade , Síndromes Neoplásicas Hereditárias/etiologia , Neoplasias Pancreáticas/etiologia , Linhagem , Estrutura Quaternária de ProteínaRESUMO
Transforming growth factor ß-activated kinase 1 (TAK1) mediates multiple biological processes through the nuclear factor κ-light-chain-enhancer of activated B cells (NF-κB) and the mitogen-activated protein kinase (MAPK) signaling pathways. TAK1 activation is tightly regulated by its binding partners (TABs). In particular, binding with TAB2 is crucial for cardiovascular development and extracellular matrix (ECM) homeostasis. In our previous work, we reported a novel multisystem disorder associated with the heterozygous TAB2 c.1398dup variant. Here, we dissect the functional effects of this variant in order to understand its molecular pathogenesis. We demonstrate that TAB2 c.1398dup considerably undergoes to nonsense-mediated messenger RNA decay and encodes a truncated protein that loses its ability to bind TAK1. We also show an alteration of the TAK1 autophosphorylation status and of selected downstream signaling pathways in patients' fibroblasts. Immunofluorescence analyses and ECM-related polymerase chain reaction-array panels highlight that patient fibroblasts display ECM disorganization and altered expression of selected ECM components and collagen-related pathways. In conclusion, we deeply dissect the molecular pathogenesis of the TAB2 c.1398dup variant and show that the resulting phenotype is well explained by TAB2 loss-of-function. Our data also offer initial insights on the ECM homeostasis impairment as a molecular mechanism probably underlying a multisystem disorder linked to TAB2.
Assuntos
Proteínas Adaptadoras de Transdução de Sinal/genética , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Matriz Extracelular/metabolismo , Variação Genética , Haploinsuficiência , Homeostase , Proteínas Adaptadoras de Transdução de Sinal/química , Sequência de Aminoácidos , Linhagem Celular , Proliferação de Células , Análise Mutacional de DNA , Fibroblastos/metabolismo , Humanos , MAP Quinase Quinase Quinases/metabolismo , Mutação , Degradação do RNAm Mediada por Códon sem Sentido , Fosforilação , Ligação Proteica , Transdução de SinaisRESUMO
Genetic syndromes are frequently associated with Intellectual Disability (ID), as well as craniofacial dysmorphisms. A group of ID syndromes with typical abnormal face related to chromatin remodeling defects, have been recognized, coining the term chromatinopathies. This is a molecular heterogeneous subset of congenital disorders caused by mutations of the various components of the Chromatin-Marking System (CMS), including modifiers of DNA and chromatin remodelers. We performed a phenotypic study on a sample of 120 individuals harboring variants in genes codifying for the histones enzymes, using the DeepGestalt technology. Three experiments (two multiclass comparison experiments and a frontal face-crop analysis) were conducted, analyzing respectively a total of 181 pediatric images in the first comparison experiment and 180 in the second, all individuals belonging predominantly to Caucasian population. The classification results were expressed in terms of the area under the curve (AUC) of the receiver-operating-characteristic curve (ROC). Significant values of AUC and low p-values were registered for all syndromes in the three experiments, in comparison with each other, with other ID syndromes characterized by recognizable craniofacial dysmorphisms and with unaffected controls. Final findings indicated that this group of diseases is characterized by distinctive dysmorphisms, which result pathognomonic. A correct interrogation and use of adequate informatics aids, could become a valid support for clinicians.
Assuntos
Fácies , Estudos de Associação Genética , Predisposição Genética para Doença , Deficiência Intelectual/diagnóstico , Deficiência Intelectual/genética , Fenótipo , Criança , Pré-Escolar , Estudos de Coortes , Diagnóstico por Imagem , Feminino , Estudos de Associação Genética/métodos , Humanos , Processamento de Imagem Assistida por Computador , Masculino , Curva ROCRESUMO
OBJECTIVES: This study is aimed at identifying discrete severity classes among adults with hypermobile Ehlers-Danlos syndrome (hEDS)/hypermobility spectrum disorders (HSD). METHODS: Subjects were selected according to the old and new nomenclatures and all completed a set of questionnaires exploring pain, fatigue, dysautonomic symptoms, coordination and attention/concentration deficits and quality of life in general. Data were investigated by hierarchical clustering on principal components. Cluster comparisons were then performed by using the two-sample unpaired t test and the standardized mean difference was reported as a measure of effect size. Conditional classification tree analysis and multivariable logistic regression were carried out in order to identify the profiles that were at higher risk to belong to the more severe cluster. Weighted linear combination was used to identify a numerical score measuring this risk. RESULTS: A total of 105 patients were selected and distributed in two distinct severity groups. These groups were statistically separated on the basis of 47 of 59 items/characteristics. One group featured the worse values of most questionnaire items (complex/severe cluster) and the other was dominated by the better values (simplex/milder cluster). Only three items were able to stratify patients according to their risk to belong to the complex cluster. A severity score was then constructed on these three items. CONCLUSION: Adults with hEDS/HSD can be separated in two severity classes, which do not mirror either the old or new criteria for hEDS. The identified severity score could allow a bi-dimensional approach to adults with hEDS/HSD for optimal management planning.
Assuntos
Síndrome de Ehlers-Danlos/classificação , Instabilidade Articular/classificação , Índice de Gravidade de Doença , Adulto , Artralgia/classificação , Artralgia/etiologia , Síndrome de Ehlers-Danlos/complicações , Síndrome de Ehlers-Danlos/patologia , Fadiga/classificação , Fadiga/etiologia , Feminino , Humanos , Itália , Instabilidade Articular/complicações , Instabilidade Articular/patologia , Modelos Lineares , Masculino , Pessoa de Meia-Idade , Projetos Piloto , Disautonomias Primárias/classificação , Disautonomias Primárias/etiologia , Qualidade de Vida , Inquéritos e Questionários , SíndromeRESUMO
Recessive variants in LTBP2 are associated with eye-restricted phenotypes including (a) primary congenital glaucoma and (b) microspherophakia/megalocornea and ectopia lentis with/without secondary glaucoma. Nosology of LTBP2 pathology in humans is apparently in contrast with the consolidated evidence of a wide expression of this gene in the developing embryo. Accordingly, in previously published patients with LTBP2-related eye disease, additional extraocular findings have been occasionally reported and include, among others, high-arched palate, tall stature, and variable cardiac involvement. Anyway, no emphasis was put on such systemic manifestations. Here, we report two unrelated Roma/Gypsy patients first ascertained for a multisystem disorder mainly characterized by primary congenital glaucoma, complex congenital heart defect, tall stature, long fingers, skin striae and dystrophic scarring, and resembling Marfan syndrome. Heart involvement was severe with polyvalvular heart dysplasia in one, and transposition of great arteries, thoracic arterial tortuosity, polyvalvular heart dysplasia, and neo-aortic root dilatation in the other. Both patients were homozygous for the recurrent c.895C>T[p.(R299X)] variant, typically found in individuals of Roma/Gypsy descent with an eye-restricted phenotype. Our findings point out LTBP2 as responsible of a systemic phenotype coherent with the community of syndromes related to anomalies in genes involved in the TGFß-pathway. Among these disorders, LTBP2-related systemic disease emerges as a distinct condition with expanding prognostic implications and autosomal recessive inheritance.
Assuntos
Glaucoma/genética , Cardiopatias Congênitas/genética , Proteínas de Ligação a TGF-beta Latente/genética , Síndrome de Marfan/genética , Adolescente , Criança , Doenças da Córnea/genética , Doenças da Córnea/fisiopatologia , Ectopia do Cristalino/genética , Ectopia do Cristalino/fisiopatologia , Oftalmopatias Hereditárias/genética , Oftalmopatias Hereditárias/fisiopatologia , Feminino , Doenças Genéticas Ligadas ao Cromossomo X/genética , Doenças Genéticas Ligadas ao Cromossomo X/fisiopatologia , Glaucoma/diagnóstico por imagem , Glaucoma/fisiopatologia , Coração/diagnóstico por imagem , Coração/fisiopatologia , Cardiopatias Congênitas/diagnóstico por imagem , Cardiopatias Congênitas/fisiopatologia , Homozigoto , Humanos , Iris/anormalidades , Iris/fisiopatologia , Masculino , Síndrome de Marfan/fisiopatologia , Fenótipo , Roma (Grupo Étnico)/genética , Fator de Crescimento Transformador beta/genéticaRESUMO
Pain is necessary to alert us to actual or potential tissue damage. Specialized nerve cells in the body periphery, so called nociceptors, are fundamental to mediate pain perception and humans without pain perception are at permanent risk for injuries, burns and mutilations. Pain insensitivity can be caused by sensory neurodegeneration which is a hallmark of hereditary sensory and autonomic neuropathies (HSANs). Although mutations in several genes were previously associated with sensory neurodegeneration, the etiology of many cases remains unknown. Using next generation sequencing in patients with congenital loss of pain perception, we here identify bi-allelic mutations in the FLVCR1 (Feline Leukemia Virus subgroup C Receptor 1) gene, which encodes a broadly expressed heme exporter. Different FLVCR1 isoforms control the size of the cytosolic heme pool required to sustain metabolic activity of different cell types. Mutations in FLVCR1 have previously been linked to vision impairment and posterior column ataxia in humans, but not to HSAN. Using fibroblasts and lymphoblastoid cell lines from patients with sensory neurodegeneration, we here show that the FLVCR1-mutations reduce heme export activity, enhance oxidative stress and increase sensitivity to programmed cell death. Our data link heme metabolism to sensory neuron maintenance and suggest that intracellular heme overload causes early-onset degeneration of pain-sensing neurons in humans.
Assuntos
Proteínas de Membrana Transportadoras/genética , Degeneração Neural/genética , Estresse Oxidativo/genética , Dor/genética , Receptores Virais/genética , Apoptose/genética , Linhagem Celular , Exoma/genética , Feminino , Fibroblastos/metabolismo , Fibroblastos/patologia , Mutação da Fase de Leitura/genética , Heme/genética , Humanos , Imunoprecipitação , Masculino , Degeneração Neural/patologia , Nociceptores/metabolismo , Nociceptores/patologia , Dor/patologia , Cultura Primária de Células , Células Receptoras Sensoriais/metabolismo , Células Receptoras Sensoriais/patologiaRESUMO
The 2017 nosology defines the new criteria for hypermobile Ehlers-Danlos syndrome (hEDS), which is now considered one end of a continuous spectrum encompassing isolated, nonsyndromic joint hypermobility (JH) and hypermobility spectrum disorders (HSDs). Preliminary data indicate a link between JH and neurodevelopmental disorders and, in particular, developmental coordination disorder (DCD) in children. Assessing DCD in adults is difficult and the recently described functional difficulties questionnaire 9 (FDQ-9) is one of the few available tools. The aims of this study are to (a) validate FDQ-9 written in Italian and present normal values in 230 Italian controls; (b) explore the relationship of FDQ-9 with the brief pain inventory, composite autonomic symptom score 31, multidimensional fatigue inventory, attention deficit/hyperactivity disorder self-report version 1.1, and the SF-36 for quality of life in 105 Italian adults with hEDS/HSD. Validation of the FDQ-9 in Italian was carried out by translation, cross-cultural adaptation and test/retest reliability analysis. A case-control study was performed comparing the FDQ-9 outcome between 105 patients and 105 sex- and age-matched controls. Fifty-nine percent of the patients resulted positive compared to the 3.8% of controls (p value < .00001). In patients, FDQ-9 positive result associated with positive attention deficit/hyperactivity disorder self-report version 1.1 (OR = 4.04). Multivariate regression analysis comparing FDQ-9 with the other questionnaires demonstrated a strong association between positive FDQ-9 and the number of painful joints. Our preliminary data open wider management and therapeutic perspectives for coordination difficulties in hypermobile individuals.
Assuntos
Síndrome de Ehlers-Danlos/fisiopatologia , Síndrome de Ehlers-Danlos/psicologia , Inquéritos e Questionários/normas , Adolescente , Adulto , Estudos de Casos e Controles , Feminino , Humanos , Itália , Masculino , Pessoa de Meia-Idade , Qualidade de Vida/psicologia , Reprodutibilidade dos Testes , AutorrelatoRESUMO
Mutations of SLC40A1 encoding ferroportin (Fpn), the unique cellular iron exporter, severely affect iron homeostasis causing type 4 hereditary hemochromatosis, an autosomal dominant iron overload condition with variable phenotypic manifestations. This disease can be classified as type 4A, better known as "ferroportin disease", which is due to "loss of function" mutations that lead to decreased iron export from cells, or as type 4B hemochromatosis, which is caused by "gain of function" mutations, conferring partial or complete resistance to hepcidin-mediated Fpn degradation. In this work, we discuss clinical and molecular findings on a group of patients in whom a SLC40A1 single copy missense variant was identified. Three novel variants, p.D181N, p.G204R and p.R296Q were functionally characterized. Fpn D181N and R296Q mutants can be classified as full or partial loss of function, respectively. Replacement of G204 with arginine appears to cause a more complex defect with impact both on iron export function and hepcidin sensitivity. This finding confirms the difficulty of predicting the effect of a mutation on the molecular properties of Fpn in order to provide an exhaustive explanation to the wide variability of the phenotype in type 4 hereditary hemochromatosis.