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1.
Genet Med ; 2019 Jul 31.
Artigo em Inglês | MEDLINE | ID: mdl-31363182

RESUMO

PURPOSE: Kabuki syndrome (KS) (OMIM 147920 and 300867) is a rare genetic disorder characterized by specific facial features, intellectual disability, and various malformations. Immunopathological manifestations seem prevalent and increase the morbimortality. To assess the frequency and severity of the manifestations, we measured the prevalence of immunopathological manifestations as well as genotype-phenotype correlations in KS individuals from a registry. METHODS: Data were for 177 KS individuals with KDM6A or KMT2D pathogenic variants. Questionnaires to clinicians were used to assess the presence of immunodeficiency and autoimmune diseases both on a clinical and biological basis. RESULTS: Overall, 44.1% (78/177) and 58.2% (46/79) of KS individuals exhibited infection susceptibility and hypogammaglobulinemia, respectively; 13.6% (24/177) had autoimmune disease (AID; 25.6% [11/43] in adults), 5.6% (10/177) with ≥2 AID manifestations. The most frequent AID manifestations were immune thrombocytopenic purpura (7.3% [13/177]) and autoimmune hemolytic anemia (4.0% [7/177]). Among nonhematological manifestations, vitiligo was frequent. Immune thrombocytopenic purpura was frequent with missense versus other types of variants (p = 0.027). CONCLUSION: The high prevalence of immunopathological manifestations in KS demonstrates the importance of systematic screening and efficient preventive management of these treatable and sometimes life-threatening conditions.

3.
Clin Genet ; 96(4): 309-316, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31237352

RESUMO

Pycnodysostosis is a lysosomal autosomal recessive skeletal dysplasia characterized by osteosclerosis, short stature, acro-osteolysis, facial features and an increased risk of fractures. The clinical heterogeneity of the disease and its rarity make it difficult to provide patients an accurate prognosis, as well as appropriate care and follow-up. French physicians from the OSCAR network have been asked to fill out questionnaires collecting molecular and clinical data for 27 patients issued from 17 unrelated families. All patients showed short stature (mean = -3.5 SD) which was more severe in females (P = .006). The mean fracture rate was moderate (0.21 per year), with four fractures in total average. About 75% underwent at least one surgery, with an average number of 2.1 interventions per patient. About 50% required non-invasive assisted ventilation due to sleep apnea (67%). About 29% showed psychomotor difficulties and 33% needed a school assistant or adapted schooling. No patient had any psychological evaluation or follow-up. Molecular data were available for 14 families. Growth hormone administration was efficient on linear growth in 40% of cases. We propose several axis of management, such as systematic cerebral MRI for Chiari malformation screening at diagnosis and regular psychological follow-up.

4.
Hum Mutat ; 2019 Jun 23.
Artigo em Inglês | MEDLINE | ID: mdl-31230393

RESUMO

Human retrocopies, that is messenger RNA transcripts benefitting from the long interspersed element 1 machinery for retrotransposition, may have specific consequences for genomic testing. Next genetration sequencing (NGS) techniques allow the detection of such mobile elements but they may be misinterpreted as genomic duplications or be totally overlooked. We report eight observations of retrocopies detected during diagnostic NGS analyses of targeted gene panels, exome, or genome sequencing. For seven cases, while an exons-only copy number gain was called, read alignment inspection revealed a depth of coverage shift at every exon-intron junction where indels were also systematically called. Moreover, aberrant chimeric read pairs spanned entire introns or were paired with another locus for terminal exons. The 8th retrocopy was present in the reference genome and thus showed a normal NGS profile. We emphasize the existence of retrocopies and strategies to accurately detect them at a glance during genetic testing and discuss pitfalls for genetic testing.

5.
Am J Hum Genet ; 104(6): 1223-1232, 2019 Jun 06.
Artigo em Inglês | MEDLINE | ID: mdl-31130282

RESUMO

Aberrant signaling through pathways controlling cell response to extracellular stimuli constitutes a central theme in disorders affecting development. Signaling through RAS and the MAPK cascade controls a variety of cell decisions in response to cytokines, hormones, and growth factors, and its upregulation causes Noonan syndrome (NS), a developmental disorder whose major features include a distinctive facies, a wide spectrum of cardiac defects, short stature, variable cognitive impairment, and predisposition to malignancies. NS is genetically heterogeneous, and mutations in more than ten genes have been reported to underlie this disorder. Despite the large number of genes implicated, about 10%-20% of affected individuals with a clinical diagnosis of NS do not have mutations in known RASopathy-associated genes, indicating that additional unidentified genes contribute to the disease, when mutated. By using a mixed strategy of functional candidacy and exome sequencing, we identify RRAS2 as a gene implicated in NS in six unrelated subjects/families. We show that the NS-causing RRAS2 variants affect highly conserved residues localized around the nucleotide binding pocket of the GTPase and are predicted to variably affect diverse aspects of RRAS2 biochemical behavior, including nucleotide binding, GTP hydrolysis, and interaction with effectors. Additionally, all pathogenic variants increase activation of the MAPK cascade and variably impact cell morphology and cytoskeletal rearrangement. Finally, we provide a characterization of the clinical phenotype associated with RRAS2 mutations.

6.
J Med Genet ; 56(8): 526-535, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-30923172

RESUMO

BACKGROUND: Balanced chromosomal rearrangements associated with abnormal phenotype are rare events, but may be challenging for genetic counselling, since molecular characterisation of breakpoints is not performed routinely. We used next-generation sequencing to characterise breakpoints of balanced chromosomal rearrangements at the molecular level in patients with intellectual disability and/or congenital anomalies. METHODS: Breakpoints were characterised by a paired-end low depth whole genome sequencing (WGS) strategy and validated by Sanger sequencing. Expression study of disrupted and neighbouring genes was performed by RT-qPCR from blood or lymphoblastoid cell line RNA. RESULTS: Among the 55 patients included (41 reciprocal translocations, 4 inversions, 2 insertions and 8 complex chromosomal rearrangements), we were able to detect 89% of chromosomal rearrangements (49/55). Molecular signatures at the breakpoints suggested that DNA breaks arose randomly and that there was no major influence of repeated elements. Non-homologous end-joining appeared as the main mechanism of repair (55% of rearrangements). A diagnosis could be established in 22/49 patients (44.8%), 15 by gene disruption (KANSL1, FOXP1, SPRED1, TLK2, MBD5, DMD, AUTS2, MEIS2, MEF2C, NRXN1, NFIX, SYNGAP1, GHR, ZMIZ1) and 7 by position effect (DLX5, MEF2C, BCL11B, SATB2, ZMIZ1). In addition, 16 new candidate genes were identified. Systematic gene expression studies further supported these results. We also showed the contribution of topologically associated domain maps to WGS data interpretation. CONCLUSION: Paired-end WGS is a valid strategy and may be used for structural variation characterisation in a clinical setting.

7.
Genet Med ; 21(7): 1667-1671, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-30783266

RESUMO

The article has been corrected to account for one patient being investigated through genome sequencing rather than exome sequencing as originally published; thus amendments to the Abstract and Methods have been made as well as addition of the relevant authors and acknowledgment.

8.
Eur J Med Genet ; 2019 Jan 19.
Artigo em Inglês | MEDLINE | ID: mdl-30664951

RESUMO

Mutations in LZTR1, already known to be causal in familial schwannomatosis type 2, have been recently involved in a small proportion of patients with autosomal dominant and autosomal recessive Noonan syndrome. LZTR1 is also a driver gene in non syndromal glioblastoma. We report a 26-year-old patient with typical Noonan syndrome, and the dominantly transmitted c.850C > T (p.(Arg284Cys)) variant in LZTR1. An oligoastrocytoma was diagnosed in the patient at the age of 22 years; recurrence of the tumor occurred at age 26, as a ganglioblastoma. The patient had been transiently treated with growth hormone between ages 15 and 17. Considering the implication of LZTR1 in sporadic tumors of the nervous system, we hypothesize that gliomas are a possible complication of LZTR1-related Noonan syndrome. This report also supports a possible link between occurrence of a cerebral tumor in Noonan syndrome and a previous treatment with growth hormone.

9.
Genet Med ; 2018 Oct 25.
Artigo em Inglês | MEDLINE | ID: mdl-30356099

RESUMO

PURPOSE: Germline WWOX pathogenic variants have been associated with disorder of sex differentiation (DSD), spinocerebellar ataxia (SCA), and WWOX-related epileptic encephalopathy (WOREE syndrome). We review clinical and molecular data on WWOX-related disorders, further describing WOREE syndrome and phenotype/genotype correlations. METHODS: We report clinical and molecular findings in 20 additional patients from 18 unrelated families with WOREE syndrome and biallelic pathogenic variants in the WWOX gene. Different molecular screening approaches were used (quantitative polymerase chain reaction/multiplex ligation-dependent probe amplification [qPCR/MLPA], array comparative genomic hybridization [array-CGH], Sanger sequencing, epilepsy gene panel, exome sequencing). RESULTS: Two copy-number variations (CNVs) or two single-nucleotide variations (SNVs) were found respectively in four and nine families, with compound heterozygosity for one SNV and one CNV in five families. Eight novel missense pathogenic variants have been described. By aggregating our patients with all cases reported in the literature, 37 patients from 27 families with WOREE syndrome are known. This review suggests WOREE syndrome is a very severe epileptic encephalopathy characterized by absence of language development and acquisition of walking, early-onset drug-resistant seizures, ophthalmological involvement, and a high likelihood of premature death. The most severe clinical presentation seems to be associated with null genotypes. CONCLUSION: Germline pathogenic variants in WWOX are clearly associated with a severe early-onset epileptic encephalopathy. We report here the largest cohort of individuals with WOREE syndrome.

10.
Mol Syndromol ; 9(4): 190-196, 2018 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-30140196

RESUMO

EFEMP2 mutations are known to be responsible for autosomal recessive cutis laxa type 1B (ARCL1B), a rare multisystem disease affecting skin, skeleton, and vascular structures. We report 2 additional related cases of ARCL1B of particular severity leading to termination of pregnancy. Cardinal signs of this connective tissue disease were already seen during the second trimester of pregnancy, then confirmed and clarified at autopsy. Anomalies included cutis laxa, arachnodactyly, clubfoot, wormian bones, moderate bowing of long bones with slender bone trabeculae, rib fractures, undermuscularized diaphragm, hiatal hernia, and arterial tortuosity with thick vascular walls and disorganized elastic fibers. Sequencing of the EFEMP2 gene revealed a novel homozygous nonsense mutation: c.639C>A (p.Cys213*). We performed a thorough histological analysis and discuss differential diagnoses, genotype-phenotype correlations, and the challenge of prenatal diagnosis of this disease.

11.
Eur J Hum Genet ; 26(11): 1611-1622, 2018 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-30006632

RESUMO

Acrodysostosis (MIM 101800) is a dominantly inherited condition associating (1) skeletal features (short stature, facial dysostosis, and brachydactyly with cone-shaped epiphyses), (2) resistance to hormones and (3) possible intellectual disability. Acroscyphodysplasia (MIM 250215) is characterized by growth retardation, brachydactyly, and knee epiphyses embedded in cup-shaped metaphyses. We and others have identified PDE4D or PRKAR1A variants in acrodysostosis; PDE4D variants have been reported in three cases of acroscyphodysplasia. Our study aimed at reviewing the clinical and molecular findings in a cohort of 27 acrodysostosis and 5 acroscyphodysplasia cases. Among the acrodysostosis cases, we identified 9 heterozygous de novo PRKAR1A variants and 11 heterozygous PDE4D variants. The 7 patients without variants presented with symptoms of acrodysostosis (brachydactyly and cone-shaped epiphyses), but none had the characteristic facial dysostosis. In the acroscyphodysplasia cases, we identified 2 PDE4D variants. For 2 of the 3 negative cases, medical records revealed early severe infection, which has been described in some reports of acroscyphodysplasia. Subdividing our series of acrodysostosis based on the disease-causing gene, we confirmed genotype-phenotype correlations. Hormone resistance was consistently observed in patients carrying PRKAR1A variants, whereas no hormone resistance was observed in 9 patients with PDE4D variants. All patients with PDE4D variants shared characteristic facial features (midface hypoplasia with nasal hypoplasia) and some degree of intellectual disability. Our findings of PDE4D variants in two cases of acroscyphodysplasia support that PDE4D may be responsible for this severe skeletal dysplasia. We eventually emphasize the importance of some specific assessments in the long-term follow up, including cardiovascular and thromboembolic risk factors.

12.
Eur J Hum Genet ; 26(7): 996-1006, 2018 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-29695756

RESUMO

High-throughput sequencing (HTS) of human genome coding regions allows the simultaneous screen of a large number of genes, significantly improving the diagnosis of non-syndromic intellectual disabilities (ID). HTS studies permit the redefinition of the phenotypical spectrum of known disease-causing genes, escaping the clinical inclusion bias of gene-by-gene Sanger sequencing. We studied a cohort of 903 patients with ID not reminiscent of a well-known syndrome, using an ID-targeted HTS of several hundred genes and found de novo heterozygous variants in TCF4 (transcription factor 4) in eight novel patients. Piecing together the patients from this study and those from previous large-scale unbiased HTS studies, we estimated the rate of individuals with ID carrying a disease-causing TCF4 mutation to 0.7%. So far, TCF4 molecular abnormalities were known to cause a syndromic form of ID, Pitt-Hopkins syndrome (PTHS), which combines severe ID, developmental delay, absence of speech, behavioral and ventilation disorders, and a distinctive facial gestalt. Therefore, we reevaluated ten patients carrying a pathogenic or likely pathogenic variant in TCF4 (eight patients included in this study and two from our previous ID-HTS study) for PTHS criteria defined by Whalen and Marangi. A posteriori, five patients had a score highly evocative of PTHS, three were possibly consistent with this diagnosis, and two had a score below the defined PTHS threshold. In conclusion, these results highlight TCF4 as a frequent cause of moderate to profound ID and broaden the clinical spectrum associated to TCF4 mutations to nonspecific ID.

13.
NPJ Genom Med ; 2: 32, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-29263841

RESUMO

Phelan-McDermid syndrome (PMS) is characterized by a variety of clinical symptoms with heterogeneous degrees of severity, including intellectual disability (ID), absent or delayed speech, and autism spectrum disorders (ASD). It results from a deletion of the distal part of chromosome 22q13 that in most cases includes the SHANK3 gene. SHANK3 is considered a major gene for PMS, but the factors that modulate the severity of the syndrome remain largely unknown. In this study, we investigated 85 patients with different 22q13 rearrangements (78 deletions and 7 duplications). We first explored the clinical features associated with PMS, and provide evidence for frequent corpus callosum abnormalities in 28% of 35 patients with brain imaging data. We then mapped several candidate genomic regions at the 22q13 region associated with high risk of clinical features, and suggest a second locus at 22q13 associated with absence of speech. Finally, in some cases, we identified additional clinically relevant copy-number variants (CNVs) at loci associated with ASD, such as 16p11.2 and 15q11q13, which could modulate the severity of the syndrome. We also report an inherited SHANK3 deletion transmitted to five affected daughters by a mother without ID nor ASD, suggesting that some individuals could compensate for such mutations. In summary, we shed light on the genotype-phenotype relationship of patients with PMS, a step towards the identification of compensatory mechanisms for a better prognosis and possibly treatments of patients with neurodevelopmental disorders.

14.
Am J Med Genet A ; 173(8): 2081-2087, 2017 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-28573701

RESUMO

Interstitial 2p15p16.1 microdeletion is a rare chromosomal syndrome previously reported in 33 patients. It is characterized by intellectual disability, developmental delay, autism spectrum disorders, microcephaly, short stature, dysmorphic features, and multiple congenital organ defects. It is defined as a contiguous gene syndrome and two critical regions have been proposed at 2p15 and 2p16.1 loci. Nevertheless, patients with deletion of both critical regions shared similar features of the phenotype and the correlation genotype-phenotype is still unclear. We review all published cases and describe three additional patients, to define the phenotype-genotype correlation more precisely. We reported on two patients including the first prenatal case described so far, carrying a 2p15 deletion affecting two genes: XPO1 and part of USP34. Both patients shared similar features including facial dysmorphism and cerebral abnormalities. We considered the genes involved in the deleted segment to further understand the abnormal phenotype. The third case we described here was a 4-year-old boy with a heterozygous de novo 427 kb deletion encompassing BCL11A and PAPOLG at 2p16.1. He displayed speech delay, autistic traits, and motor stereotypies associated with brain structure abnormalities. We discuss the contribution of the genes included in the deletion to the abnormal phenotype. Our three new patients compared to previous cases, highlighted that despite two critical regions, both distal deletion at 2p16.1 and proximal deletion at 2p15 are associated with phenotypes that are very close to each other. Finally, we also discuss the genetic counseling of this microdeletion syndrome particularly in the course of prenatal diagnosis.


Assuntos
Anormalidades Múltiplas/genética , Deleção Cromossômica , Deficiências do Desenvolvimento/genética , Microcefalia/genética , Anormalidades Múltiplas/diagnóstico por imagem , Anormalidades Múltiplas/fisiopatologia , Encéfalo/diagnóstico por imagem , Encéfalo/fisiopatologia , Proteínas de Transporte/genética , Pré-Escolar , Cromossomos Humanos Par 2/genética , Deficiências do Desenvolvimento/diagnóstico por imagem , Deficiências do Desenvolvimento/fisiopatologia , Feminino , Humanos , Lactente , Carioferinas/genética , Imagem por Ressonância Magnética , Masculino , Microcefalia/diagnóstico por imagem , Microcefalia/fisiopatologia , Proteínas Nucleares/genética , Fenótipo , Receptores Citoplasmáticos e Nucleares/genética , Proteases Específicas de Ubiquitina/genética
15.
Acta Neuropathol Commun ; 5(1): 36, 2017 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-28460636

RESUMO

Congenital hydrocephalus is considered as either acquired due to haemorrhage, infection or neoplasia or as of developmental nature and is divided into two subgroups, communicating and obstructive. Congenital hydrocephalus is either syndromic or non-syndromic, and in the latter no cause is found in more than half of the patients. In patients with isolated hydrocephalus, L1CAM mutations represent the most common aetiology. More recently, a founder mutation has also been reported in the MPDZ gene in foetuses presenting massive hydrocephalus, but the neuropathology remains unknown. We describe here three novel homozygous null mutations in the MPDZ gene in foetuses whose post-mortem examination has revealed a homogeneous phenotype characterized by multiple ependymal malformations along the aqueduct of Sylvius, the third and fourth ventricles as well as the central canal of the medulla, consisting in multifocal rosettes with immature cell accumulation in the vicinity of ependymal lining early detached from the ventricular zone. MPDZ also named MUPP1 is an essential component of tight junctions which are expressed from early brain development in the choroid plexuses and ependyma. Alterations in the formation of tight junctions within the ependyma very likely account for the lesions observed and highlight for the first time that primary multifocal ependymal malformations of the ventricular system is genetically determined in humans. Therefore, MPDZ sequencing should be performed when neuropathological examination reveals multifocal ependymal rosette formation within the aqueduct of Sylvius, of the third and fourth ventricles and of the central canal of the medulla.


Assuntos
Proteínas de Transporte/genética , Epêndima/anormalidades , Doenças Fetais/genética , Hidrocefalia/genética , Mutação com Perda de Função , Adulto , Epêndima/diagnóstico por imagem , Família , Feminino , Doenças Fetais/diagnóstico por imagem , Doenças Fetais/etiologia , Doenças Fetais/patologia , Homozigoto , Humanos , Hidrocefalia/diagnóstico por imagem , Hidrocefalia/etiologia , Hidrocefalia/patologia
16.
Am J Med Genet A ; 170(11): 2847-2859, 2016 11.
Artigo em Inglês | MEDLINE | ID: mdl-27605097

RESUMO

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.


Assuntos
Anormalidades Múltiplas/diagnóstico , Anormalidades Múltiplas/genética , Doenças do Desenvolvimento Ósseo/diagnóstico , Doenças do Desenvolvimento Ósseo/genética , Estudos de Associação Genética , Deficiência Intelectual/diagnóstico , Deficiência Intelectual/genética , Mutação , Proteínas Repressoras/genética , Anormalidades Dentárias/diagnóstico , Anormalidades Dentárias/genética , Adolescente , Adulto , Idoso , Alelos , Substituição de Aminoácidos , Criança , Pré-Escolar , Deleção Cromossômica , Cromossomos Humanos Par 16 , Hibridização Genômica Comparativa , Facies , Feminino , Humanos , Lactente , Masculino , Pessoa de Meia-Idade , Fenótipo , Estudos Retrospectivos , Adulto Jovem
17.
Hum Mutat ; 37(9): 847-64, 2016 09.
Artigo em Inglês | MEDLINE | ID: mdl-27302555

RESUMO

Kabuki syndrome (KS) is a rare but recognizable condition that consists of a characteristic face, short stature, various organ malformations, and a variable degree of intellectual disability. Mutations in KMT2D have been identified as the main cause for KS, whereas mutations in KDM6A are a much less frequent cause. Here, we report a mutation screening in a case series of 347 unpublished patients, in which we identified 12 novel KDM6A mutations (KS type 2) and 208 mutations in KMT2D (KS type 1), 132 of them novel. Two of the KDM6A mutations were maternally inherited and nine were shown to be de novo. We give an up-to-date overview of all published mutations for the two KS genes and point out possible mutation hot spots and strategies for molecular genetic testing. We also report the clinical details for 11 patients with KS type 2, summarize the published clinical information, specifically with a focus on the less well-defined X-linked KS type 2, and comment on phenotype-genotype correlations as well as sex-specific phenotypic differences. Finally, we also discuss a possible role of KDM6A in Kabuki-like Turner syndrome and report a mutation screening of KDM6C (UTY) in male KS patients.


Assuntos
Anormalidades Múltiplas/genética , Proteínas de Ligação a DNA/genética , Face/anormalidades , Doenças Hematológicas/genética , Histona Desmetilases/genética , Mutação , Proteínas de Neoplasias/genética , Proteínas Nucleares/genética , Doenças Vestibulares/genética , Anormalidades Múltiplas/patologia , Face/patologia , Feminino , Genes Ligados ao Cromossomo X , Predisposição Genética para Doença , Doenças Hematológicas/patologia , Humanos , Masculino , Herança Materna , Síndrome de Noonan/genética , Análise de Sequência de DNA , Doenças Vestibulares/patologia
18.
PLoS Genet ; 12(3): e1005894, 2016 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-26967905

RESUMO

Ciliopathies are a group of genetic multi-systemic disorders related to dysfunction of the primary cilium, a sensory organelle present at the cell surface that regulates key signaling pathways during development and tissue homeostasis. In order to identify novel genes whose mutations would cause severe developmental ciliopathies, >500 patients/fetuses were analyzed by a targeted high throughput sequencing approach allowing exome sequencing of >1200 ciliary genes. NEK8/NPHP9 mutations were identified in five cases with severe overlapping phenotypes including renal cystic dysplasia/hypodysplasia, situs inversus, cardiopathy with hypertrophic septum and bile duct paucity. These cases highlight a genotype-phenotype correlation, with missense and nonsense mutations associated with hypodysplasia and enlarged cystic organs, respectively. Functional analyses of NEK8 mutations in patient fibroblasts and mIMCD3 cells showed that these mutations differentially affect ciliogenesis, proliferation/apoptosis/DNA damage response, as well as epithelial morphogenesis. Notably, missense mutations exacerbated some of the defects due to NEK8 loss of function, highlighting their likely gain-of-function effect. We also showed that NEK8 missense and loss-of-function mutations differentially affect the regulation of the main Hippo signaling effector, YAP, as well as the expression of its target genes in patient fibroblasts and renal cells. YAP imbalance was also observed in enlarged spheroids of Nek8-invalidated renal epithelial cells grown in 3D culture, as well as in cystic kidneys of Jck mice. Moreover, co-injection of nek8 MO with WT or mutated NEK8-GFP RNA in zebrafish embryos led to shortened dorsally curved body axis, similar to embryos injected with human YAP RNA. Finally, treatment with Verteporfin, an inhibitor of YAP transcriptional activity, partially rescued the 3D spheroid defects of Nek8-invalidated cells and the abnormalities of NEK8-overexpressing zebrafish embryos. Altogether, our study demonstrates that NEK8 human mutations cause major organ developmental defects due to altered ciliogenesis and cell differentiation/proliferation through deregulation of the Hippo pathway.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/genética , Cílios/genética , Fosfoproteínas/genética , Doenças Renais Policísticas/genética , Proteínas Quinases/genética , Proteínas Adaptadoras de Transdução de Sinal/antagonistas & inibidores , Proteínas Adaptadoras de Transdução de Sinal/biossíntese , Animais , Diferenciação Celular/genética , Cílios/patologia , Feminino , Estudos de Associação Genética , Humanos , Rim/metabolismo , Rim/patologia , Camundongos , Morfogênese/genética , Mutação , Quinases Relacionadas a NIMA , Fosfoproteínas/antagonistas & inibidores , Fosfoproteínas/biossíntese , Doenças Renais Policísticas/patologia , Porfirinas/administração & dosagem , Transdução de Sinais , Verteporfina , Peixe-Zebra
19.
JIMD Rep ; 29: 109-113, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-26920903

RESUMO

The C10orf2 gene encodes Twinkle, a protein involved in mitochondrial DNA (mtDNA) replication. Twinkle mutations cause mtDNA deletion or depletion and are associated with a large spectrum of clinical symptoms including dominant progressive external ophthalmoplegia (adPEO), infantile-onset spinocerebellar ataxia (IOSCA), and early-onset encephalopathy. The diagnosis remains difficult because of the wide range of symptoms and lack of association with specific metabolic changes. We report herein a child with early-onset encephalopathy, unusual abnormal movements, deafness, and axonal neuropathy. All laboratory investigations were normal with the exceptions of high alpha-fetoprotein levels and an abnormal glycosylation profile. These abnormal parameters resulted in misdiagnosis as a previously unidentified congenital disorder of glycosylation (CDG) type I syndrome. Whole exome sequencing revealed two point mutations in C10orf2 that were confirmed by Sanger sequencing; neither had been previously reported. This report enlarges the clinical phenotype of Twinkle mutations and suggests that an abnormal glycosylation profile suggestive of CDG type I associated with high blood alpha-fetoprotein levels without obvious cause should prompt Twinkle sequencing.

20.
Eur J Endocrinol ; 174(5): 641-50, 2016 May.
Artigo em Inglês | MEDLINE | ID: mdl-26903553

RESUMO

BACKGROUND: Growth patterns of patients with Noonan syndrome (NS) were established before the involved genes were identified. OBJECTIVE: The goal of this study was to compare growth parameters according to genotype in patients with NS. SUBJECTS AND METHODS: The study population included 420 patients (176 females and 244 males) harboring mutations in the PTPN11, SOS1, RAF1, or KRAS genes. NS-associated PTPN11 mutations (NS-PTPN11) and NS with multiple lentigines-associated PTPN11 mutations (NSML-PTPN11) were distinguished. Birth measures and height and body mass index (BMI) measures at 2, 5, 10 years, and adulthood were compared with the general population and between genotypes. RESULTS: Patients with NS were shorter at birth (mean birth length standard deviation score (SDS): -1.0 ± 1.4; P < 0.001) and throughout childhood than the healthy population, with height SDS being -2.1 ± 1.3 at 2 years, and -2.1 ± 1.2 at 5 and 10 years and adulthood (P < 0.001). At birth, patients with NS-PTPN11 were significantly shorter and thinner than patients with NSML-PTPN11, SOS1, or KRAS. Growth retardation was significantly less severe and less frequent at 2 years in patients with NSML-PTPN11 and SOS1 than in patients with NS-PTPN11 (P < 0.001 and P = 0.002 respectively). Patients with NS had lower BMI at 10 years (P < 0.001). No difference between genotypes was demonstrated. CONCLUSION: Determining the growth patterns of patients with NS according to genotype should better inform clinicians about the natural course of growth in NS so that they can optimize the follow-up and management of these patients.


Assuntos
Estatura , Índice de Massa Corporal , Peso Corporal , Genótipo , Síndrome de Noonan/genética , Síndrome de Noonan/patologia , Adulto , Fatores Etários , Peso ao Nascer , Criança , Pré-Escolar , Feminino , Humanos , Recém-Nascido , Masculino , Adulto Jovem
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