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1.
Clin Genet ; 100(4): 462-467, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-34212369

RESUMO

Hydrolethalus syndrome (HLS) is a rare lethal fetal malformation disorder related to ciliogenesis disruption. This condition is more frequent in Finland where a founder missense variant in the HYLS1 gene was identified. No other HYLS1 variant has hitherto been implicated in HLS. We report two unrelated French fetuses presenting with a phenotype of HLS with brain abnormalities, limbs malformations with pre and postaxial hexadactyly and abnormal genitalia. These two fetuses have compound heterozygous variants in HYLS1. The first allele carries the same Finnish missense variant (NM_145014.2: c.632A > G, p.[Asp211Gly]) in both fetuses and the second allele carries a new missense variant (c.662G > C, p.[Arg221Pro]) in the first fetus, and a new nonsense variant (c.613C > T, p.[Arg205*]) in the second fetus. This is the first report of HYLS1 mutated cases outside Finland. Both cases presented here are consistent with HLS with additional malformations, allowing expansion of the phenotypic presentation previously described.


Assuntos
Predisposição Genética para Doença , Variação Genética , Deformidades Congênitas da Mão/diagnóstico , Deformidades Congênitas da Mão/genética , Cardiopatias Congênitas/diagnóstico , Cardiopatias Congênitas/genética , Hidrocefalia/diagnóstico , Hidrocefalia/genética , Fenótipo , Proteínas/genética , Alelos , Substituição de Aminoácidos , Autopsia , Hibridização Genômica Comparativa , Feminino , Feto , Estudos de Associação Genética , Genótipo , Humanos , Imuno-Histoquímica , Linhagem , Gravidez , Ultrassonografia Pré-Natal
2.
Clin Genet ; 98(3): 261-273, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32621347

RESUMO

Megacystis-microcolon-intestinal-hypoperistalsis syndrome (MMIHS) is a severe congenital visceral myopathy characterized by an abdominal distension due to a large non-obstructed urinary bladder, a microcolon and intestinal hypo- or aperistalsis. Most of the patients described to date carry a sporadic heterozygous variant in ACTG2. More recently, recessive forms have been reported and mutations in MYH11, LMOD1, MYLK and MYL9 have been described at the molecular level. In the present report, we describe five patients carrying a recurrent heterozygous variant in ACTG2. Exome sequencing performed in four families allowed us to identify the genetic cause in three. In two families, we identified variants in MMIHS causal genes, respectively a nonsense homozygous variant in MYH11 and a previously described homozygous deletion in MYL9. Finally, we identified compound heterozygous variants in a novel candidate gene, PDCL3, c.[143_144del];[380G>A], p.[(Tyr48Ter)];[(Cys127Tyr)]. After cDNA analysis, a complete absence of PDLC3 expression was observed in affected individuals, indicating that both mutated transcripts were unstable and prone to mediated mRNA decay. PDCL3 encodes a protein involved in the folding of actin, a key step in thin filament formation. Presumably, loss-of-function of this protein affects the contractility of smooth muscle tissues, making PDCL3 an excellent candidate gene for autosomal recessive forms of MMIHS.


Assuntos
Anormalidades Múltiplas/genética , Proteínas de Transporte/genética , Colo/anormalidades , Predisposição Genética para Doença , Pseudo-Obstrução Intestinal/genética , Proteínas do Tecido Nervoso/genética , Bexiga Urinária/anormalidades , Anormalidades Múltiplas/patologia , Feto Abortado , Actinas/genética , Colo/patologia , Feminino , Homozigoto , Humanos , Recém-Nascido , Pseudo-Obstrução Intestinal/patologia , Masculino , Mutação/genética , Cadeias Pesadas de Miosina/genética , Cadeias Leves de Miosina/genética , Linhagem , Bexiga Urinária/patologia , Sequenciamento do Exoma
3.
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 , Fatores de Transcrição , Verteporfina , Proteínas de Sinalização YAP , Peixe-Zebra
4.
Am J Hum Genet ; 97(2): 311-8, 2015 Aug 06.
Artigo em Inglês | MEDLINE | ID: mdl-26166481

RESUMO

KIAA0586, the human ortholog of chicken TALPID3, is a centrosomal protein that is essential for primary ciliogenesis. Its disruption in animal models causes defects attributed to abnormal hedgehog signaling; these defects include polydactyly and abnormal dorsoventral patterning of the neural tube. Here, we report homozygous mutations of KIAA0586 in four families affected by lethal ciliopathies ranging from a hydrolethalus phenotype to short-rib polydactyly. We show defective ciliogenesis, as well as abnormal response to SHH-signaling activation in cells derived from affected individuals, consistent with a role of KIAA0586 in primary cilia biogenesis. Whereas centriolar maturation seemed unaffected in mutant cells, we observed an abnormal extended pattern of CEP290, a centriolar satellite protein previously associated with ciliopathies. Our data show the crucial role of KIAA0586 in human primary ciliogenesis and subsequent abnormal hedgehog signaling through abnormal GLI3 processing. Our results thus establish that KIAA0586 mutations cause lethal ciliopathies.


Assuntos
Proteínas de Ciclo Celular/genética , Transtornos da Motilidade Ciliar/genética , Códon sem Sentido/genética , Deformidades Congênitas da Mão/genética , Cardiopatias Congênitas/genética , Hidrocefalia/genética , Fenótipo , Síndrome de Costela Curta e Polidactilia/genética , Sequência de Bases , Transtornos da Motilidade Ciliar/patologia , Europa Oriental , Evolução Fatal , Efeito Fundador , Humanos , Funções Verossimilhança , Dados de Sequência Molecular , Linhagem , Análise de Sequência de DNA
5.
Am J Med Genet A ; 176(7): 1610-1613, 2018 07.
Artigo em Inglês | MEDLINE | ID: mdl-29704304

RESUMO

Ciliopathies comprise a group of clinically heterogeneous and overlapping disorders with a wide spectrum of phenotypes ranging from prenatal lethality to adult-onset disorders. Pathogenic variants in more than 100 ciliary protein-encoding genes have been described, most notably those involved in intraflagellar transport (IFT) which comprises two protein complexes, responsible for retrograde (IFT-A) and anterograde transport (IFT-B). Here we describe a fetus with an unclassified severe ciliopathy phenotype including short ribs, polydactyly, bilateral renal agenesis, and imperforate anus, with compound heterozygosity for c.118_125del, p.(Thr40Glyfs*11) and a c.352 +1G > T in IFT27, which encodes a small GTPase component of the IFT-B complex. We conclude that bilateral renal agenesis is a rare feature of this severe ciliopathy and this report highlights the phenotypic overlap of Pallister-Hall syndrome and ciliopathies. The phenotype in patients with IFT27 gene variants is wide ranging from Bardet-Biedl syndrome to a lethal phenotype.


Assuntos
Ciliopatias/patologia , Anormalidades Congênitas/patologia , Doenças Fetais/patologia , Nefropatias/congênito , Rim/anormalidades , Mutação , Proteínas rab de Ligação ao GTP/genética , Ciliopatias/genética , Anormalidades Congênitas/genética , Evolução Fatal , Feminino , Doenças Fetais/genética , Humanos , Rim/patologia , Nefropatias/genética , Nefropatias/patologia , Masculino , Linhagem
6.
Birth Defects Res A Clin Mol Teratol ; 106(1): 36-46, 2016 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-26663670

RESUMO

BACKGROUND: Corpus callosum malformation (CCM) is the most frequent brain malformation observed at birth. Because CCM is a highly heterogeneous condition, the prognosis of fetuses diagnosed prenatally remains uncertain, making prenatal counseling difficult. METHODS AND RESULTS: We evaluated retrospectively a total of 138 fetuses, 117 with CCM observed on prenatal imaging examination, and 21 after postmortem autopsy. On ultrasound and/or magnetic resonance imaging, CCM was either isolated (N = 40) or associated with other neurological (N = 57) or extra cerebral findings (N = 21/20, respectively). RESULTS: Most fetuses (N = 132) remained without a diagnosis at the time of pregnancy termination. This emphasizes the need to establish a neuropathological classification and to perform a genomic screening using comparative genomic hybridization. A neuropathological examination performed on 138 cases revealed a spectrum of CCMs, classified as follows: agenesis of corpus callosum (55), CC hypoplasia (30), CC dysmorphism (24), and CCM associated with a malformation of cortical development (29). Of interest, after fetopathological examination, only 16/40 malformations were classified as isolated, highlighting the importance of the autopsy following termination of pregnancy. Among the 138 cases, the underlying etiology was found in 46 cases: diabetes (one case), cytomegalovirus infection (one case), 23 chromosome abnormalities, and 21 mendelian conditions. CONCLUSION: In our series of 138 cases of CCM, prenatal and postmortem examinations identified a variety of genetic causes. However, no diagnosis could be established in 67% of cases. The classification based on the underlying neurodevelopmental defects paves the way for further genetic studies and genotype-phenotype correlations.


Assuntos
Agenesia do Corpo Caloso/diagnóstico , Aberrações Cromossômicas , Corpo Caloso/patologia , Mutação , Proteínas do Tecido Nervoso/genética , Aborto Eugênico , Adulto , Agenesia do Corpo Caloso/genética , Agenesia do Corpo Caloso/patologia , Autopsia , Hibridização Genômica Comparativa , Corpo Caloso/metabolismo , Feminino , Feto , Expressão Gênica , Humanos , Masculino , Gravidez , Estudos Retrospectivos , Ultrassonografia Pré-Natal
7.
Harefuah ; 154(10): 632-6, 676, 2015 Oct.
Artigo em Hebraico | MEDLINE | ID: mdl-26742224

RESUMO

BACKGROUND: Meckel-Gruber syndrome (MKS) is a lethal rare inherited autosomal recessive disease. The syndrome is characterized by multiple congenital anomalies including polycystic kidneys, occipital encephalocele and polydactyly. The presence of two out of these anomalies is sufficient for a definitive diagnosis. At least 11 genes have been reported to-date to underlie MKS. METHODS: In the current study we have retrospectively analyzed all the families at the Ha'Emek Medical Center in which the diagnosis of MKS was determined. RESULTS: In total, 17 affected individuals are reported, originating from 12 sibships. The diagnoses were conducted or suspected by prenatal sonography, and some of the newborns were examined. Polycystic kidneys were present in 94% of cases, occipital encephalocele in 82% and polydactyly in about half of all cases. The underlying genetic cause was identified in 11 of our families, comprising mutations in 7 different genes, revealing high genetic heterogeneity. CONCLUSION: The identification of the genetic basis of MKS in our region allows focused and data-based genetic counseling and serves as an important tool for reproductive decisions, including the prevention of recurrence of pregnancies affected with this lethal syndrome. In the near future we plan to study the prevalence of the different MKS mutations found in each community in order to consider the expansion of national genetic screening in high risk populations.


Assuntos
Árabes/genética , Transtornos da Motilidade Ciliar/epidemiologia , Encefalocele/epidemiologia , Doenças Renais Policísticas/epidemiologia , Transtornos da Motilidade Ciliar/genética , Transtornos da Motilidade Ciliar/fisiopatologia , Encefalocele/genética , Encefalocele/fisiopatologia , Feminino , Humanos , Incidência , Recém-Nascido , Israel/epidemiologia , Masculino , Mutação , Doenças Renais Policísticas/genética , Doenças Renais Policísticas/fisiopatologia , Gravidez , Diagnóstico Pré-Natal/métodos , Retinose Pigmentar , Estudos Retrospectivos
8.
Hum Mutat ; 35(1): 137-46, 2014 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-24166846

RESUMO

Joubert syndrome (JS) is characterized by a distinctive cerebellar structural defect, namely the << molar tooth sign >>. JS is genetically heterogeneous, involving 20 genes identified to date, which are all required for cilia biogenesis and/or function. In a consanguineous family with JS associated with optic nerve coloboma, kidney hypoplasia, and polydactyly, combined exome sequencing and mapping identified a homozygous splice-site mutation in PDE6D, encoding a prenyl-binding protein. We found that pde6d depletion in zebrafish leads to renal and retinal developmental anomalies and wild-type but not mutant PDE6D is able to rescue this phenotype. Proteomic analysis identified INPP5E, whose mutations also lead to JS or mental retardation, obesity, congenital retinal dystrophy, and micropenis syndromes, as novel prenyl-dependent cargo of PDE6D. Mutant PDE6D shows reduced binding to INPP5E, which fails to localize to primary cilia in patient fibroblasts and tissues. Furthermore, mutant PDE6D is unable to bind to GTP-bound ARL3, which acts as a cargo-release factor for PDE6D-bound INPP5E. Altogether, these results indicate that PDE6D is required for INPP5E ciliary targeting and suggest a broader role for PDE6D in targeting other prenylated proteins to the cilia. This study identifies PDE6D as a novel JS disease gene and provides the first evidence of prenyl-binding-dependent trafficking in ciliopathies.


Assuntos
Doenças Cerebelares/genética , Doenças Cerebelares/metabolismo , Cílios/metabolismo , Nucleotídeo Cíclico Fosfodiesterase do Tipo 6/genética , Nucleotídeo Cíclico Fosfodiesterase do Tipo 6/metabolismo , Anormalidades do Olho/genética , Anormalidades do Olho/metabolismo , Doenças Renais Císticas/genética , Doenças Renais Císticas/metabolismo , Monoéster Fosfórico Hidrolases/genética , Monoéster Fosfórico Hidrolases/metabolismo , Retina/anormalidades , Fatores de Ribosilação do ADP/metabolismo , Anormalidades Múltiplas , Animais , Cerebelo/anormalidades , Exoma , Feminino , Predisposição Genética para Doença , Homozigoto , Humanos , Masculino , Modelos Moleculares , Linhagem , Prenilação de Proteína , Proteômica , Retina/metabolismo , Análise de Sequência de DNA , Peixe-Zebra/anormalidades , Peixe-Zebra/genética , Proteínas de Peixe-Zebra/genética , Proteínas de Peixe-Zebra/metabolismo
9.
J Med Genet ; 49(11): 713-20, 2012 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-23125460

RESUMO

BACKGROUND: Acrocallosal syndrome (ACLS) is a rare recessive disorder characterised by corpus callosum agenesis or hypoplasia, craniofacial dysmorphism, duplication of the hallux, postaxial polydactyly, and severe mental retardation. Recently, we identified mutations in KIF7, a key component of the Sonic hedgehog pathway, as being responsible for this syndrome. METHODS: We sequenced KIF7 in five suspected ACLS cases, one fetus and four patients, based on facial dysmorphism and brain anomalies. RESULTS: Seven mutations were identified at the KIF7 locus in these five cases, six of which are novel. We describe the first four compound heterozygous cases. In all patients, the diagnosis was suspected based on the craniofacial features, despite the absence of corpus callosum anomaly in one and of polydactyly in another. Hallux duplication was absent in 4/5 cases. CONCLUSIONS: These results show that ACLS has a variable expressivity and can be diagnosed even in the absence of the two major features, namely polydactyly or agenesis or hypoplasia of the corpus callosum. Facial dysmorphism with hypertelorism and prominent forehead in all the cases, as well as vermis dysgenesis with brainstem anomalies (molar tooth sign), strongly indicated the diagnosis. KIF7 should be tested in less typical patients in whom craniofacial features are suggestive of ACLS.


Assuntos
Síndrome Acrocalosal/genética , Cinesinas/genética , Mutação , Síndrome Acrocalosal/diagnóstico , Síndrome Acrocalosal/fisiopatologia , Agenesia do Corpo Caloso/diagnóstico , Agenesia do Corpo Caloso/fisiopatologia , Pré-Escolar , Feminino , Feto , Humanos , Deficiência Intelectual/diagnóstico , Deficiência Intelectual/fisiopatologia , Masculino , Pessoa de Meia-Idade , Fenótipo , Polidactilia/diagnóstico , Polidactilia/fisiopatologia
10.
Acta Neuropathol Commun ; 11(1): 29, 2023 02 20.
Artigo em Inglês | MEDLINE | ID: mdl-36803301

RESUMO

Congenital hydrocephalus is a common condition caused by the accumulation of cerebrospinal fluid in the ventricular system. Four major genes are currently known to be causally involved in hydrocephalus, either isolated or as a common clinical feature: L1CAM, AP1S2, MPDZ and CCDC88C. Here, we report 3 cases from 2 families with congenital hydrocephalus due to bi-allelic variations in CRB2, a gene previously reported to cause nephrotic syndrome, variably associated with hydrocephalus. While 2 cases presented with renal cysts, one case presented with isolated hydrocephalus. Neurohistopathological analysis allowed us to demonstrate that, contrary to what was previously proposed, the pathological mechanisms underlying hydrocephalus secondary to CRB2 variations are not due to stenosis but to atresia of both Sylvius Aqueduct and central medullar canal. While CRB2 has been largely shown crucial for apico-basal polarity, immunolabelling experiments in our fetal cases showed normal localization and level of PAR complex components (PKCι and PKCζ) as well as of tight (ZO-1) and adherens (ß-catenin and N-Cadherin) junction molecules indicating a priori normal apicobasal polarity and cell-cell adhesion of the ventricular epithelium suggesting another pathological mechanism. Interestingly, atresia but not stenosis of Sylvius aqueduct was also described in cases with variations in MPDZ and CCDC88C encoding proteins previously linked functionally to the Crumbs (CRB) polarity complex, and all 3 being more recently involved in apical constriction, a process crucial for the formation of the central medullar canal. Overall, our findings argue for a common mechanism of CRB2, MPDZ and CCDC88C variations that might lead to abnormal apical constriction of the ventricular cells of the neural tube that will form the ependymal cells lining the definitive central canal of the medulla. Our study thus highlights that hydrocephalus related to CRB2, MPDZ and CCDC88C constitutes a separate pathogenic group of congenital non-communicating hydrocephalus with atresia of both Sylvius aqueduct and central canal of the medulla.


Assuntos
Aqueduto do Mesencéfalo , Hidrocefalia , Humanos , Aqueduto do Mesencéfalo/patologia , Polaridade Celular/genética , Hidrocefalia/patologia , Proteínas , Proteínas de Transporte/genética , Proteínas de Membrana/genética , Proteínas dos Microfilamentos , Peptídeos e Proteínas de Sinalização Intracelular
11.
J Med Genet ; 47(12): 848-52, 2010 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-20805367

RESUMO

BACKGROUND: Bardet-Biedl syndrome (BBS) is a genetically heterogeneous, multisystemic disorder characterised by progressive retinal dystrophy, obesity, hypogenitalism, learning difficulties, renal abnormalities and postaxial polydactyly, with only the last two antenatally observable. BBS is inherited as an autosomal recessive disorder, and 14 genes have been identified to date (BBS1-BBS14). In addition, a complex digenic inheritance has been established in some families. Mutations of the BBS10 gene on chromosome 12q21.2 account for 20% of BBS cases. METHODS: Given the fact that mutations in BBS genes have already been found in Meckel-like fetuses, and in light of the major contribution of BBS10 to BBS, the BBS10 gene was sequenced in 20 fetal cases and a child diagnosed antenatally presenting with characteristic renal anomalies and polydactyly, but without biliary dysgenesis. RESULTS: Recessive mutations were identified at the BBS10 locus in five cases: four fetuses and a child. Interestingly, one of them had situs ambiguus, a rare feature in BBS. In the child, BBS gene screening identified a heterozygous BBS6 nonsense mutation in addition to the homozygous BBS10 mutation, in accordance with the suggested multigenic inheritance of the disease. CONCLUSIONS: These results confirm that BBS is underdiagnosed antenatally and should systematically be suspected in fetuses with severe cystic kidneys leading to oligoamnios and fetal or perinatal death. Moreover, this study confirms the high frequency of BBS10 mutations, particularly of the p.Cys91LeufsX5 allele, including severe lethal cases.


Assuntos
Chaperoninas do Grupo II/genética , Doenças Renais Císticas/genética , Mutação/genética , Sequência de Aminoácidos , Sequência de Bases , Chaperoninas , Criança , Pré-Escolar , Feminino , Chaperoninas do Grupo II/química , Humanos , Doenças Renais Císticas/patologia , Masculino , Dados de Sequência Molecular , Adulto Jovem
12.
Hum Mutat ; 31(10): 1134-41, 2010 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-20690116

RESUMO

Rare lethal disease gene identification remains a challenging issue, but it is amenable to new techniques in high-throughput sequencing (HTS). Cerebral proliferative glomeruloid vasculopathy (PGV), or Fowler syndrome, is a severe autosomal recessive disorder of brain angiogenesis, resulting in abnormally thickened and aberrant perforating vessels leading to hydranencephaly. In three multiplex consanguineous families, genome-wide SNP analysis identified a locus of 14 Mb on chromosome 14. In addition, 280 consecutive SNPs were identical in two Turkish families unknown to be related, suggesting a founder mutation reducing the interval to 4.1 Mb. To identify the causative gene, we then specifically enriched for this region with sequence capture and performed HTS in a proband of seven families. Due to technical constraints related to the disease, the average coverage was only 7×. Nonetheless, iterative bioinformatic analyses of the sequence data identified mutations and a large deletion in the FLVCR2 gene, encoding a 12 transmembrane domain-containing putative transporter. A striking absence of alpha-smooth muscle actin immunostaining in abnormal vessels in fetal PGV brains, suggests a deficit in pericytes, cells essential for capillary stabilization and remodeling during brain angiogenesis. This is the first lethal disease-causing gene to be identified by comprehensive HTS of an entire linkage interval.


Assuntos
Ensaios de Triagem em Larga Escala/métodos , Hidranencefalia/genética , Proteínas de Membrana Transportadoras/genética , Mutação , Receptores Virais/genética , Deleção de Sequência , Doenças Vasculares/genética , Encéfalo/irrigação sanguínea , Cromossomos Humanos Par 14/genética , Consanguinidade , Feto/irrigação sanguínea , Ligação Genética , Humanos , Hidrocefalia/genética , Proteínas de Membrana Transportadoras/química , Neovascularização Patológica , Linhagem , Polimorfismo de Nucleotídeo Único , Receptores Virais/química , Análise de Sequência de DNA
13.
Hum Mutat ; 31(5): E1319-31, 2010 May.
Artigo em Inglês | MEDLINE | ID: mdl-20232449

RESUMO

Human ciliopathies are hereditary conditions caused by defects of proteins expressed at the primary cilium. Among ciliopathies, Joubert syndrome and related disorders (JSRD), Meckel syndrome (MKS) and nephronophthisis (NPH) present clinical and genetic overlap, being allelic at several loci. One of the most interesting gene is TMEM67, encoding the transmembrane protein meckelin. We performed mutation analysis of TMEM67 in 341 probands, including 265 JSRD representative of all clinical subgroups and 76 MKS fetuses. We identified 33 distinct mutations, of which 20 were novel, in 8/10 (80%) JS with liver involvement (COACH phenotype) and 12/76 (16%) MKS fetuses. No mutations were found in other JSRD subtypes, confirming the strong association between TMEM67 mutations and liver involvement. Literature review of all published TMEM67 mutated cases was performed to delineate genotype-phenotype correlates. In particular, comparison of the types of mutations and their distribution along the gene in lethal versus non lethal phenotypes showed in MKS patients a significant enrichment of missense mutations falling in TMEM67 exons 8 to 15, especially when in combination with a truncating mutation. These exons encode for a region of unknown function in the extracellular domain of meckelin.


Assuntos
Anormalidades Múltiplas/genética , Doenças Renais Císticas/genética , Cirrose Hepática/genética , Proteínas de Membrana/genética , Mutação/genética , Análise Mutacional de DNA , Feminino , Genótipo , Humanos , Doenças Renais Císticas/patologia , Cirrose Hepática/patologia , Fenótipo , Gravidez , Diagnóstico Pré-Natal
14.
Hum Mutat ; 30(11): 1574-82, 2009 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-19777577

RESUMO

Meckel-Gruber syndrome (MKS) is a lethal fetal disorder characterized by diffuse renal cystic dysplasia, polydactyly, a brain malformation that is usually occipital encephalocele, and/or vermian agenesis, with intrahepatic biliary duct proliferation. Joubert syndrome (JBS) is a viable neurological disorder with a characteristic "molar tooth sign" (MTS) on axial images reflecting cerebellar vermian hypoplasia/dysplasia. Both conditions are classified as ciliopathies with an autosomal recessive mode of inheritance. Allelism of MKS and JBS has been reported for TMEM67/MKS3, CEP290/MKS4, and RPGRIP1L/MKS5. Recently, one homozygous splice mutation with a founder effect was reported in the CC2D2A gene in Finnish fetuses with MKS, defining the 6th locus for MKS. Shortly thereafter, CC2D2A mutations were also reported in JBS. The analysis of the CC2D2A gene in our series of MKS fetuses, identified 14 novel truncating mutations in 11 cases. These results confirm the involvement of CC2D2A in MKS and reveal a major contribution of CC2D2A to the disease. We also identified three missense CC2D2A mutations in two JBS cases. Therefore, and in accordance with the data reported regarding RPGRIP1L, our results indicate phenotype-genotype correlations, as missense and presumably hypomorphic mutations lead to JBS while all null alleles lead to MKS.


Assuntos
Mutação , Doenças do Sistema Nervoso/genética , Proteínas/genética , Alelos , Estudos de Coortes , Proteínas do Citoesqueleto , Regulação da Expressão Gênica no Desenvolvimento , Genes Recessivos , Estudos de Associação Genética , Genótipo , Humanos , Hibridização In Situ , Masculino , Doenças do Sistema Nervoso/patologia , Fenótipo , Proteínas/metabolismo , Splicing de RNA , Síndrome
15.
Birth Defects Res ; 110(7): 598-602, 2018 04 17.
Artigo em Inglês | MEDLINE | ID: mdl-29356416

RESUMO

BACKGROUND: The RTTN gene encodes Rotatin, a large centrosomal protein involved in ciliary functions. RTTN mutations have been reported in seven families and are associated with two phenotypes: polymicrogyria associated with seizures and primary microcephaly associated with primordial dwarfism. CASE: A targeted exome sequencing of morbid genes causing cerebral malformations identified novel RTTN compound heterozygous mutations in a family where three pregnancies were terminated because a severe fetal microcephaly was diagnosed. An autopsy performed on the second sib showed moderate growth restriction and a microcephaly with simplified gyral pattern. The histopathological study discovered a malformed cortical plate. CONCLUSIONS: The present study confirms the involvement of RTTN gene mutations in microcephaly with simplified gyral pattern and describes the observed abnormal neuropathological findings.


Assuntos
Encéfalo/patologia , Proteínas de Transporte/genética , Microcefalia/genética , Mutação , Proteínas de Ciclo Celular , Humanos , Microcefalia/patologia
16.
Eur J Med Genet ; 61(10): 585-595, 2018 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-29605658

RESUMO

Mutations in CPLANE1 (previously known as C5orf42) cause Oral-Facial-Digital Syndrome type VI (OFD6) as well as milder Joubert syndrome (JS) phenotypes. Seven new cases from five unrelated families diagnosed with pure OFD6 were systematically examined. Based on the clinical manifestations of these patients and those described in the literature, we revised the diagnostic features of OFD6 and include the seven most common characteristics: 1) molar tooth sign, 2) tongue hamartoma and/or lobulated tongue, 3) additional frenula, 4) mesoaxial polydactyly of hands, 5) preaxial polydactyly of feet, 6) syndactyly and/or bifid toe, and 7) hypothalamic hamartoma. By whole or targeted exome sequencing, we identified seven novel germline recessive mutations in CPLANE1, including missense, nonsense, frameshift and canonical splice site variants, all causing OFD6 in these patients. Since CPLANE1 is also mutated in JS patients, we examined whether a genotype-phenotype correlation could be established. We gathered and compared 46 biallelic CPLANE1 mutations reported in 32 JS and 26 OFD6 patients. Since no clear correlation between paired genotypes and clinical outcomes could be determined, we concluded that patient's genetic background and gene modifiers may modify the penetrance and expressivity of CPLANE1 causal alleles. To conclude, our study provides a comprehensive view of the phenotypic range, the genetic basis and genotype-phenotype association in OFD6 and JS. The updated phenotype scoring system together with the identification of new CPLANE1 mutations will help clinicians and geneticists reach a more accurate diagnosis for JS-related disorders.


Assuntos
Anormalidades Múltiplas/genética , Cerebelo/anormalidades , Anormalidades do Olho/genética , Mutação em Linhagem Germinativa , Doenças Renais Císticas/genética , Proteínas de Membrana/genética , Síndromes Orofaciodigitais/genética , Retina/anormalidades , Anormalidades Múltiplas/diagnóstico , Adolescente , Adulto , Criança , Pré-Escolar , Anormalidades do Olho/diagnóstico , Feminino , Humanos , Lactente , Recém-Nascido , Doenças Renais Císticas/diagnóstico , Masculino , Pessoa de Meia-Idade , Síndromes Orofaciodigitais/diagnóstico , Penetrância
17.
J Med Case Rep ; 9: 254, 2015 Nov 05.
Artigo em Inglês | MEDLINE | ID: mdl-26541515

RESUMO

INTRODUCTION: Joubert syndrome is a rare congenital disorder characterized by brain malformation, developmental delay with hypotonia, ocular motor apraxia, and breathing abnormalities. Joubert syndrome is a genetically highly heterogeneous ciliopathy disorder with 23 identified causative genes. The diagnosis is based on brain imaging showing the "molar tooth sign" with cerebellar vermis agenesis. We describe a consanguineous Moroccan family with three affected siblings (18-year-old boy, 13-year-old girl, and 10-year-old boy) showing typical signs of Joubert syndrome, and attempt to identify the underlying genetic defect in this family. METHODS: We performed genome-wide homozygosity mapping using a high-resolution array followed by targeted Sanger sequencing to identify the causative gene. RESULTS: This approach found three homozygous regions, one including the AHI1 gene. Direct sequencing of the 26 coding exons of AHI1 revealed a homozygous mutation (p.Thr304AsnfsX6) located in exon 7 present in the three Joubert syndrome-affected Moroccan siblings. Of more interest, this truncating mutation was previously reported in patients with compound heterozygous Joubert syndrome originating from Spain (one patient) and from the Netherlands (two patients), suggesting a possible founder effect or mutational hotspot. CONCLUSIONS: Combined homozygosity mapping and targeted sequencing allowed the rapid detection of the disease-causing mutation in the AHI1 gene in this family affected with a highly genetically heterogeneous disorder. Carriers of the same truncating mutation (p.Thr304AsnfsX6), originating from Spain and the Netherlands, presented variable clinical characteristics, thereby corroborating the extreme heterogeneity of Joubert syndrome.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/genética , Doenças Cerebelares/genética , Cerebelo/anormalidades , Retina/anormalidades , Anormalidades Múltiplas/genética , Proteínas Adaptadoras de Transporte Vesicular , Adolescente , Criança , Anormalidades do Olho/genética , Feminino , Heterozigoto , Humanos , Doenças Renais Císticas/genética , Imageamento por Ressonância Magnética , Masculino , Marrocos , Mutação , Linhagem
18.
Eur J Hum Genet ; 23(5): 621-7, 2015 May.
Artigo em Inglês | MEDLINE | ID: mdl-25138100

RESUMO

Joubert syndrome (JS) is a genetically heterogeneous autosomal recessive ciliopathy with 22 genes implicated to date, including a small, ciliary GTPase, ARL13B. ARL13B is required for cilia formation in vertebrates. JS patients display multiple symptoms characterized by ataxia due to the cerebellar vermis hypoplasia, and that can also include ocular abnormalities, renal cysts, liver fibrosis or polydactyly. These symptoms are shared with other ciliopathies, some of which display additional phenotypes, such as obesity. Here we identified a novel homozygous missense variant in ARL13B/JBTS8 in a JS patient who displayed retinal defects and obesity. We demonstrate the variant disrupts ARL13B function, as its expression did not rescue the mutant phenotype either in Arl13b(scorpion) zebrafish or in Arl13b(hennin) mouse embryonic fibroblasts, while the wild-type ARL13B did. Finally, we show that ARL13B is localized within the primary cilia of neonatal mouse hypothalamic neurons consistent with the known link between hypothalamic ciliary function and obesity. Thus our data identify a novel ARL13B variant that causes JS and retinopathy and suggest an extension of the phenotypic spectrum of ARL13B mutations to obesity.


Assuntos
Fatores de Ribosilação do ADP/genética , Doenças Cerebelares/diagnóstico , Doenças Cerebelares/genética , Oftalmopatias Hereditárias/diagnóstico , Oftalmopatias Hereditárias/genética , Mutação , Obesidade/genética , Fenótipo , Doenças Retinianas/genética , Fatores de Ribosilação do ADP/química , Fatores de Ribosilação do ADP/metabolismo , Sequência de Aminoácidos , Animais , Encéfalo/patologia , Biologia Computacional , Consanguinidade , Modelos Animais de Doenças , Ligação Genética , Homozigoto , Humanos , Imuno-Histoquímica , Lactente , Imageamento por Ressonância Magnética , Masculino , Camundongos , Modelos Moleculares , Dados de Sequência Molecular , Obesidade/diagnóstico , Linhagem , Conformação Proteica , Doenças Retinianas/diagnóstico , Alinhamento de Sequência , Análise de Sequência de DNA , Peixe-Zebra
19.
J Cell Biol ; 209(1): 129-42, 2015 Apr 13.
Artigo em Inglês | MEDLINE | ID: mdl-25869670

RESUMO

The Meckel syndrome (MKS) complex functions at the transition zone, located between the basal body and axoneme, to regulate the localization of ciliary membrane proteins. We investigated the role of Tmem231, a two-pass transmembrane protein, in MKS complex formation and function. Consistent with a role in transition zone function, mutation of mouse Tmem231 disrupts the localization of proteins including Arl13b and Inpp5e to cilia, resulting in phenotypes characteristic of MKS such as polydactyly and kidney cysts. Tmem231 and B9d1 are essential for each other and other complex components such as Mks1 to localize to the transition zone. As in mouse, the Caenorhabditis elegans orthologue of Tmem231 localizes to and controls transition zone formation and function, suggesting an evolutionarily conserved role for Tmem231. We identified TMEM231 mutations in orofaciodigital syndrome type 3 (OFD3) and MKS patients that compromise transition zone function. Thus, Tmem231 is critical for organizing the MKS complex and controlling ciliary composition, defects in which cause OFD3 and MKS.


Assuntos
Cílios/metabolismo , Transtornos da Motilidade Ciliar/genética , Encefalocele/genética , Proteínas de Membrana/genética , Síndromes Orofaciodigitais/genética , Doenças Renais Policísticas/genética , Animais , Células COS , Caenorhabditis elegans , Chlorocebus aethiops , Cílios/patologia , Proteínas do Citoesqueleto , Células HEK293 , Humanos , Proteínas de Membrana/fisiologia , Camundongos da Linhagem 129 , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Mutação de Sentido Incorreto , Proteínas/metabolismo , Retinose Pigmentar
20.
Eur J Hum Genet ; 21(10): 1074-8, 2013 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-23386033

RESUMO

Joubert syndrome and related disorders (JSRD) are clinically and genetically heterogeneous ciliopathies sharing a peculiar midbrain-hindbrain malformation known as the 'molar tooth sign'. To date, 19 causative genes have been identified, all coding for proteins of the primary cilium. There is clinical and genetic overlap with other ciliopathies, in particular with Meckel syndrome (MKS), that is allelic to JSRD at nine distinct loci. We previously identified the INPP5E gene as causative of JSRD in seven families linked to the JBTS1 locus, yet the phenotypic spectrum and prevalence of INPP5E mutations in JSRD and MKS remain largely unknown. To address this issue, we performed INPP5E mutation analysis in 483 probands, including 408 JSRD patients representative of all clinical subgroups and 75 MKS fetuses. We identified 12 different mutations in 17 probands from 11 JSRD families, with an overall 2.7% mutation frequency among JSRD. The most common clinical presentation among mutated families (7/11, 64%) was Joubert syndrome with ocular involvement (either progressive retinopathy and/or colobomas), while the remaining cases had pure JS. Kidney, liver and skeletal involvement were not observed. None of the MKS fetuses carried INPP5E mutations, indicating that the two ciliopathies are not allelic at this locus.


Assuntos
Doenças Cerebelares/genética , Anormalidades do Olho/genética , Frequência do Gene , Doenças Renais Císticas/genética , Mutação , Fenótipo , Monoéster Fosfórico Hidrolases/genética , Retina/anormalidades , Anormalidades Múltiplas , Adolescente , Sequência de Aminoácidos , Doenças Cerebelares/diagnóstico , Cerebelo/anormalidades , Criança , Pré-Escolar , Transtornos da Motilidade Ciliar/diagnóstico , Transtornos da Motilidade Ciliar/genética , Encefalocele/diagnóstico , Encefalocele/genética , Anormalidades do Olho/diagnóstico , Feminino , Heterozigoto , Humanos , Lactente , Doenças Renais Císticas/diagnóstico , Masculino , Dados de Sequência Molecular , Linhagem , Doenças Renais Policísticas/diagnóstico , Doenças Renais Policísticas/genética , Diagnóstico Pré-Natal , Prevalência , Retinose Pigmentar
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