Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 143
Filtrar
1.
Medicine (Baltimore) ; 99(8): e19169, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-32080096

RESUMO

INTRODUCTION: KIAA0586 variants have been associated to short-rib thoracic dysplasia, an autosomal recessive skeletal ciliopathy characterized by a narrow thorax, short limbs, and radiological skeletal abnormalities. PATIENT CONCERNS: Patients 1 and 2 were two Roma Gypsy siblings presenting thoracic dysplasia and a combination of oral cavity anomalies. DIAGNOSIS: A custom NGS gene panel, including genes associated to skeletal ciliopathies, identified the homozygous KIAA0586 splicing variant c.1815G>A (p.Gln605Gln) in both siblings, confirming the clinical diagnosis of short-rib-polydactyly. INTERVENTION: Patients were transferred to neonatal intensive care unit and received life-support treatment. OUTCOMES: Patients 1 and 2 died after few hours and 1 month of birth, respectively, because of respiratory failure related with the disease. CONCLUSION: We report two patients affected by short-rib polydactyly syndrome and overlapping phenotype with oral-facial-digital syndrome associated with the c.1815G>A variant in KIAA0586, suggesting a quite peculiar genotype-phenotype correlation.


Assuntos
Proteínas de Ciclo Celular/genética , Síndromes Orofaciodigitais/complicações , Síndromes Orofaciodigitais/genética , Síndrome de Costela Curta e Polidactilia/complicações , Síndrome de Costela Curta e Polidactilia/genética , Ciliopatias , Humanos , Recém-Nascido , Itália , Masculino , Fenótipo , Roma , Irmãos
2.
Am J Med Genet A ; 179(4): 639-644, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30767363

RESUMO

We report novel causative mutations in the IFT80 gene identified in four fetuses from two unrelated families with Beemer-Langer syndrome (BLS) or BLS-like phenotypes. We discuss the implication of the IFT80 gene in ciliopathies, and its diagnostic value for BLS among other SRPS.


Assuntos
Proteínas de Transporte/genética , Feto/patologia , Mutação , Síndrome de Costela Curta e Polidactilia/genética , Síndrome de Costela Curta e Polidactilia/patologia , Feminino , Feto/anormalidades , Feto/metabolismo , Humanos , Masculino , Linhagem , Fenótipo , Diagnóstico Pré-Natal
4.
Invest Ophthalmol Vis Sci ; 59(11): 4581-4589, 2018 09 04.
Artigo em Inglês | MEDLINE | ID: mdl-30242358

RESUMO

Purpose: Mutations in the intraflagellar transport protein 52 homolog (IFT52) gene are reported to interrupt ciliary function and cause short-rib thoracic dysplasia (SRTD), a specific form of skeletal ciliopathy. However, the roles of these mutations in retinal ciliopathy are inexplicit. We herein aim to study the impact of IFT52 mutations in retinopathies. Methods: A patient with syndromic ciliopathy, presenting mild SRTD (skeletal ciliopathy) and Liber congenital amaurosis (LCA; retinal ciliopathy), and nine unaffected family members were recruited. Comprehensive systemic evaluations, including ophthalmic tests, were received by the patient. Whole genome sequencing (WGS) was applied for genetic annotation. An in vitro cell system was employed to study the pathogenicity of the variant. Results: WGS identified a homozygous missense variation in IFT52, c.556A>G (p.T186A), carried by the patient but absent in both unaffected siblings. In silico analysis supported the pathogenic nature of this highly conserved variant. Structural analysis suggested that this substitution could generate a novel hydrogen bond between the mutated residue 186 and proline at residue 192, thus potentially interrupting the tertiary structure and the stability of the IFT52 protein. In vitro cellular study indicated that this mutation might disturb the stability of encoded IFT52 protein and dramatically disrupt cilia elongation in hTERT-RPE1 cells in a loss-of-function manner. Conclusions: This report expands ocular phenotypes of IFT52 mutation-caused ciliopathy to include retinal ciliopathy and demonstrates its deleterious nature in interrupting primary ciliary function. Our study hence highlights the need for screening for IFT52 mutations in LCA patients and ophthalmic reviews of patients carrying IFT52 mutations.


Assuntos
Proteínas de Transporte/genética , Ciliopatias/genética , Mutação de Sentido Incorreto , Degeneração Retiniana/genética , Animais , Pré-Escolar , Ciliopatias/diagnóstico , Ciliopatias/fisiopatologia , Biologia Computacional , Feminino , Técnica Indireta de Fluorescência para Anticorpo , Humanos , Immunoblotting , Amaurose Congênita de Leber/diagnóstico , Amaurose Congênita de Leber/genética , Amaurose Congênita de Leber/fisiopatologia , Camundongos , Camundongos Endogâmicos C57BL , Linhagem , Plasmídeos , Reação em Cadeia da Polimerase em Tempo Real , Degeneração Retiniana/diagnóstico , Degeneração Retiniana/fisiopatologia , Epitélio Pigmentado da Retina/patologia , Síndrome de Costela Curta e Polidactilia/diagnóstico , Síndrome de Costela Curta e Polidactilia/genética , Síndrome de Costela Curta e Polidactilia/fisiopatologia , Tomografia de Coerência Óptica , Transfecção , Sequenciamento Completo do Genoma
5.
Hum Mol Genet ; 27(19): 3377-3391, 2018 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-29982567

RESUMO

Skeletal dysplasias are a clinically and genetically heterogeneous group of bone and cartilage disorders. A total of 436 skeletal dysplasias are listed in the 2015 revised version of the nosology and classification of genetic skeletal disorders, of which nearly 20% are still genetically and molecularly uncharacterized. We report the clinical and molecular characterization of a lethal skeletal dysplasia of the short-rib group caused by mutation of the mouse Fop gene. Fop encodes a centrosomal and centriolar satellite (CS) protein. We show that Fop mutation perturbs ciliogenesis in vivo and that this leads to the alteration of the Hedgehog signaling pathway. Fop mutation reduces CSs movements and affects pericentriolar material composition, which probably participates to the ciliogenesis defect. This study highlights the role of a centrosome and CSs protein producing phenotypes in mice that recapitulate a short rib-polydactyly syndrome when mutated.


Assuntos
Ciliopatias/genética , Proteínas Proto-Oncogênicas/genética , Síndrome de Costela Curta e Polidactilia/genética , Fatores de Transcrição/genética , Animais , Centríolos/genética , Centrossomo/metabolismo , Centrossomo/patologia , Cílios/genética , Cílios/patologia , Ciliopatias/fisiopatologia , Humanos , Camundongos , Mutação , Síndrome de Costela Curta e Polidactilia/fisiopatologia
7.
Taiwan J Obstet Gynecol ; 57(1): 123-127, 2018 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-29458881

RESUMO

OBJECTIVE: We present the perinatal imaging findings and molecular genetic analysis in a fetus with short-rib polydactyly syndrome (SRPS) type III or short-rib thoracic dysplasia 3 with or without polydactyly (SRTD3). CASE REPORT: A 29-year-old, primigravid woman was referred for genetic counseling at 15 weeks of gestation because of abnormal ultrasound findings of short limbs, a narrow chest and bilateral polydactyly of the hands and feet, consistent with a diagnosis of SRPS type III. Chorionic villus sampling was performed, and targeted next-generation sequencing (NGS) was applied to analyze a panel of 25 genes including CEP120, DYNC2H1, DYNC2LI1, EVC, EVC2, FGFR2, FGFR3, HOXD10, IFT122, IFT140, IFT172, IFT52, IFT80, KIAA0586, NEK1, PAPSS2, SLC26A2, SOX9, TCTEX1D2, TCTN3, TTC21B, WDR19, WDR34, WDR35 and WDR60. The NGS analysis identified novel mutations in the DYNC2H1 gene. The fetus was compound heterozygous for a missense mutation c.8077G > T (p.Asp2693Tyr) of paternal origin in DYNC2H1 and a frameshift mutation c.11741_11742delTT (p.Phe3914X) of maternal origin in DYNC2H1. The fetus had a karyotype of 46,XY, and postnatally manifested characteristic SRPS type III phenotype. CONCLUSION: Targeted NGS is useful in genetic diagnosis of fetal skeletal dysplasia and SRPS, and the information acquired is helpful in genetic counseling.


Assuntos
Dineínas do Citoplasma/genética , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Síndrome de Costela Curta e Polidactilia/genética , Ultrassonografia Pré-Natal/métodos , Adulto , Amostra da Vilosidade Coriônica/métodos , Feminino , Feto/diagnóstico por imagem , Humanos , Mutação , Polidactilia/complicações , Polidactilia/genética , Gravidez , Síndrome de Costela Curta e Polidactilia/diagnóstico
8.
Birth Defects Res ; 110(4): 364-371, 2018 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-29359448

RESUMO

BACKGROUND: Genetic skeletal disorders (GSDs) are clinically and genetically heterogeneous with more than 350 genes accounting for the diversity of disease phenotypes. Prenatal diagnosis of these disorders has been challenging because of the limited but variable prenatal phenotypes, highlighting the need of a novel genetic approach. Short-rib polydactyly syndrome (SRPS) Type III is an autosomal recessive GSD characterized by extreme narrowness of the thorax, severely shortened tubular bones, polydactyly and multiple malformations. METHODS: Cytogenetic and molecular analyses using GTG-banding, single nucleotide polymorphism array and a novel GSDs targeted gene panel sequencing were performed in a 24 weeks fetus with increased biparietal diameter (BPD), short limbs, narrow thorax and polyhydramnios. RESULTS: No chromosomal abnormalities and pathogenic copy number variations (CNVs) were detected in the fetus. Two novel compound heterozygous mutations c.2992C > T and c.12836G > C in the DYNC2H1 gene were identified by targeted genes panel sequencing. A literature review was performed to delineate the prenatal phenotype of SRPS Type III. CONCLUSION: This is the first report of prenatal diagnosis of DYNC2H1 mutations causing SRPS Type III in a fetus with increased BPD associated with polyhydramnios in China. Our findings expand the mutation spectrum of DYNC2H1 in this rare disease and demonstrate that targeted gene panel capture followed by next-generation sequencing (NGS) is an efficient and cost-effective method to perform a molecular prenatal diagnosis of a rare genetic skeletal disorder.


Assuntos
Dineínas do Citoplasma/genética , Feto , Sequenciamento de Nucleotídeos em Larga Escala , Mutação , Poli-Hidrâmnios , Diagnóstico Pré-Natal , Síndrome de Costela Curta e Polidactilia , Feminino , Humanos , Poli-Hidrâmnios/diagnóstico , Poli-Hidrâmnios/genética , Gravidez , Síndrome de Costela Curta e Polidactilia/diagnóstico , Síndrome de Costela Curta e Polidactilia/genética
10.
Am J Med Genet A ; 176(2): 438-442, 2018 02.
Artigo em Inglês | MEDLINE | ID: mdl-29271569

RESUMO

Ciliopathies are disorders of the primary cilium that can affect almost all organs and that are characterized by pleiotropy and extensive intra- and interfamilial phenotypic variability. Accordingly, mutations in the same gene can cause different ciliopathy phenotypes of varying severity. WDR60 encodes a protein thought to play a role in the primary cilium's intraflagellar transport machinery. Mutations in this gene are a rare cause of Jeune asphyxiating thoracic dystrophy (JATD) and short-rib polydactyly syndrome (SRPS). Here we report on a milder and distinct phenotype in a consanguineous Pakistani pedigree with two adolescent sisters affected by retinal degeneration and postaxial polydactyly, but lack of any further skeletal or chondrodysplasia features. By targeted high-throughput sequencing of genes known or suspected to be involved in ciliogenesis, we detected a novel homozygous N-terminal truncating WDR60 mutation (c.44delC/p.Ala15Glufs*90) that co-segregated with the disease in the family. Our finding broadens the spectrum of WDR60-related phenotypes and shows the utility of broad multigene panels during the genetic work-up of patients with ciliopathies.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/genética , Polidactilia/genética , Degeneração Retiniana/genética , Síndrome de Costela Curta e Polidactilia/genética , Adolescente , Adulto , Cílios/genética , Cílios/patologia , Ciliopatias/genética , Ciliopatias/fisiopatologia , Síndrome de Ellis-Van Creveld/genética , Síndrome de Ellis-Van Creveld/fisiopatologia , Exoma/genética , Feminino , Homozigoto , Humanos , Masculino , Pessoa de Meia-Idade , Mutação , Linhagem , Polidactilia/fisiopatologia , Degeneração Retiniana/fisiopatologia , Costelas/fisiopatologia , Síndrome de Costela Curta e Polidactilia/fisiopatologia , Irmãos , Adulto Jovem
11.
Taiwan J Obstet Gynecol ; 56(6): 857-862, 2017 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-29241935

RESUMO

OBJECTIVE: Single-nucleotide polymorphism (SNP) microarrays and whole-exome sequencing (WES) are tools to precisely diagnose rare autosomal recessive (AR) diseases. In this study, SNP chip and WES were used to identify a mutated location in WDR34 in a baby born to consanguineous parents. CASE REPORT: The baby, born at 36 gestational weeks had a small thoracic cage, symmetric short proximal bones, and polydactyly. Radiography showed short ribs with reduced lung volume and pulmonary opacities, compatible with asphyxiating thoracic dystrophy or short rib-polydactyly syndrome (SRPS). At 4 months of age, she died of pulmonary hypoplasia and sepsis. SNP microarray and evaluation tool confirmed WDR34 as the candidate gene. WES detected an AR mutation at c.554C > T [p.Arg182Trp] in WDR34. CONCLUSION: This study was the first to identify c.544C > T [p.Arg182Trp] mutation in WDR34 in a patient with SRPS. According to the database, the homozygous mutation of c.544C > T in WDR34 was deleterious and the prevalence of heterozygous mutation was relatively higher in Asian population. More studies of this mutation in patients with SRPS are required.


Assuntos
Proteínas de Transporte/genética , Mutação , Síndrome de Costela Curta e Polidactilia/genética , Alelos , Consanguinidade , Evolução Fatal , Feminino , Humanos , Lactente , Recém-Nascido
12.
Am J Med Genet A ; 173(5): 1186-1189, 2017 May.
Artigo em Inglês | MEDLINE | ID: mdl-28370949

RESUMO

Since most short-rib polydactyly phenotypes are due to genes involved with biogenesis and maintenance of the primary cilium, this group of skeletal dysplasias was recently designated as ciliopathies with major skeletal involvement. Beemer-Langer syndrome or short-rib polydactyly type IV, was first described in 1983, and has, thus far, remained without a defined molecular basis. The most recent classification of the skeletal dysplasias referred to this phenotype as an as-yet unproven ciliopathy. IFT122 is a gene that encodes a protein responsible for the retrograde transport along the cilium; it has been associated with this group of skeletal dysplasias. To date, mutations in this gene were only found in Sensenbrenner syndrome. Using a panel of skeletal dysplasias genes, including 11 related to SRP, we identified biallelic mutations in IFT122 ([c.3184G>C];[c.3228dupG;c.3231_3233delCAT]) in a fetus with a typical phenotype of SRP-IV, finally confirmed that this phenotype is a ciliopathy and adding to the list of ciliopathies with major skeletal involvement.


Assuntos
Ciliopatias/genética , Polidactilia/genética , Proteínas/genética , Síndrome de Costela Curta e Polidactilia/genética , Alelos , Osso e Ossos/anormalidades , Osso e Ossos/fisiopatologia , Ciliopatias/fisiopatologia , Craniossinostoses/genética , Craniossinostoses/fisiopatologia , Displasia Ectodérmica/genética , Displasia Ectodérmica/fisiopatologia , Feto , Humanos , Recém-Nascido , Mutação , Polidactilia/fisiopatologia , Síndrome de Costela Curta e Polidactilia/fisiopatologia
13.
Clin Genet ; 92(2): 158-165, 2017 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-27925158

RESUMO

The short-rib polydactyly syndromes (SRPS) are autosomal recessively inherited, genetically heterogeneous skeletal ciliopathies. SRPS phenotypes were historically categorized as types I-IV, with type I first delineated by Saldino and Noonan in 1972. Characteristic findings among all forms of SRP include short horizontal ribs, short limbs and polydactyly. The SRP type I phenotype is characterized by a very small thorax, extreme micromelia, very short, poorly mineralized long bones, and multiple organ system anomalies. To date, the molecular basis of this most severe type of SRP, also known as Saldino-Noonan syndrome, has not been determined. We identified three SRP cases that fit the original phenotypic description of SRP type I. In all three cases, exome sequence analysis revealed compound heterozygosity for mutations in DYNC2H1, which encodes the main component of the retrograde IFT A motor, cytoplasmic dynein 2 heavy chain 1. Thus SRP type I, II, III and asphyxiating thoracic dystrophy (ATD), which also result from DYNC2H1 mutations. Herein we describe the phenotypic features, radiographic findings, and molecular basis of SRP type I.


Assuntos
Dineínas do Citoplasma/genética , Síndrome de Ellis-Van Creveld/genética , Predisposição Genética para Doença , Síndrome de Costela Curta e Polidactilia/genética , Síndrome de Ellis-Van Creveld/diagnóstico por imagem , Síndrome de Ellis-Van Creveld/fisiopatologia , Feminino , Feto/diagnóstico por imagem , Feto/fisiopatologia , Heterogeneidade Genética , Humanos , Recém-Nascido , Mutação , Fenótipo , Gravidez , Radiografia , Síndrome de Costela Curta e Polidactilia/diagnóstico por imagem , Síndrome de Costela Curta e Polidactilia/fisiopatologia , Sequenciamento Completo do Exoma
14.
Hum Mol Genet ; 25(18): 3998-4011, 2016 09 15.
Artigo em Inglês | MEDLINE | ID: mdl-27466187

RESUMO

The short rib polydactyly syndromes (SRPS) are a group of recessively inherited, perinatal-lethal skeletal disorders primarily characterized by short ribs, shortened long bones, varying types of polydactyly and concomitant visceral abnormalities. Mutations in several genes affecting cilia function cause SRPS, revealing a role for cilia function in skeletal development. To identify additional SRPS genes and discover novel ciliary molecules required for normal skeletogenesis, we performed exome sequencing in a cohort of patients and identified homozygosity for a missense mutation, p.E80K, in Intestinal Cell Kinase, ICK, in one SRPS family. The p.E80K mutation abolished serine/threonine kinase activity, resulting in altered ICK subcellular and ciliary localization, increased cilia length, aberrant cartilage growth plate structure, defective Hedgehog and altered ERK signalling. These data identify ICK as an SRPS-associated gene and reveal that abnormalities in signalling pathways contribute to defective skeletogenesis.


Assuntos
Anormalidades Múltiplas/genética , Proteínas Hedgehog/genética , Proteínas Serina-Treonina Quinases/genética , Síndrome de Costela Curta e Polidactilia/genética , Esqueleto/crescimento & desenvolvimento , Anormalidades Múltiplas/fisiopatologia , Cílios/genética , Cílios/patologia , Exoma/genética , Feminino , Humanos , Lactente , Sistema de Sinalização das MAP Quinases , Linhagem , Gravidez , Análise de Sequência de DNA , Síndrome de Costela Curta e Polidactilia/patologia , Transdução de Sinais , Esqueleto/anormalidades
15.
Hum Mol Genet ; 25(18): 4012-4020, 2016 09 15.
Artigo em Inglês | MEDLINE | ID: mdl-27466190

RESUMO

The short-rib polydactyly syndromes (SRPS) encompass a radiographically and genetically heterogeneous group of skeletal ciliopathies that are characterized by a long narrow chest, short extremities, and variable occurrence of polydactyly. Radiographic abnormalities include undermineralization of the calvarium, shortened and bowed appendicular bones, trident shaped acetabula and polydactyly. In a case of SRPS we identified compound heterozygosity for mutations in IFT52, which encodes a component of the anterograde intraflagellar transport complex. The IFT52 mutant cells synthesized a significantly reduced amount of IFT52 protein, leading to reduced synthesis of IFT74, IFT81, IFT88 and ARL13B, other key anterograde complex members. Ciliogenesis was also disrupted in the mutant cells, with a 60% reduction in the presence of cilia on mutant cells and loss of cilia length regulation for the cells with cilia. These data demonstrate that IFT52 is essential for anterograde complex integrity and for the biosynthesis and maintenance of cilia. The data identify a new locus for SRPS and show that IFT52 mutations result in a ciliopathy with primary effects on the skeleton.


Assuntos
Proteínas de Transporte/genética , Cílios/genética , Ciliopatias/genética , Síndrome de Costela Curta e Polidactilia/genética , Cílios/metabolismo , Ciliopatias/fisiopatologia , Proteínas do Citoesqueleto/genética , Flagelos/genética , Flagelos/patologia , Humanos , Complexos Multiproteicos/genética , Proteínas Musculares/genética , Mutação/genética , Síndrome de Costela Curta e Polidactilia/fisiopatologia , Esqueleto/crescimento & desenvolvimento , Esqueleto/metabolismo , Esqueleto/patologia , Proteínas Supressoras de Tumor/genética
16.
Genet Mol Res ; 15(2)2016 Jun 03.
Artigo em Inglês | MEDLINE | ID: mdl-27323140

RESUMO

Short rib-polydactyly syndrome type III (SRPS3) is a perinatal lethal skeletal disorder with polydactyly and multisystem organ abnormalities. While ultrasound of the fetus can detect skeletal abnormalities characteristic of SRPS3, the syndrome is often difficult to diagnose before birth. As SRPS3 is an autosomal recessive disorder, identification of the gene mutations involved could lead to the development of prenatal genetic testing as an accurate method of diagnosis. In this study, we describe genetic screening approaches to identify potential abnormalities associated with SRPS3. Karyotype analysis, array comparative genomic hybridization (aCGH), and next-generation panel sequencing were each performed on a fetus showing signs of the disorder, as well as on the mother and father. Karyotype and aCGH results revealed no abnormalities. However, next-generation panel sequencing identified novel mutations in the DYNC2H1 gene. The fetus was compound heterozygous for both a missense mutation c.8313A > T and a frameshift mutation c.10711_10714delTTTA in the DYNC2H1 gene, which were inherited from the mother and father, respectively. These variants were further confirmed using Sanger sequencing and have not been previously reported. Our study indicates the utility of using next-generation panel sequencing in screening for novel disease-associated mutations.


Assuntos
Hibridização Genômica Comparativa , Dineínas do Citoplasma/genética , Predisposição Genética para Doença , Síndrome de Costela Curta e Polidactilia/genética , Adulto , Feminino , Feto , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Cariótipo , Mutação , Linhagem , Síndrome de Costela Curta e Polidactilia/diagnóstico por imagem , Síndrome de Costela Curta e Polidactilia/patologia
17.
Birth Defects Res A Clin Mol Teratol ; 106(7): 549-62, 2016 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-26970085

RESUMO

BACKGROUND: The short-rib polydactyly (SRP) syndromes are rare skeletal dysplasias caused by abnormalities in primary cilia, sometimes associated with visceral malformations. METHODS: The pathogenesis of ductal plate malformation (DPM) varies in different syndromes and has not been investigated in SRP. We have studied liver development in five SRP fetuses and pancreatic development in one SRP fetus, with genetically confirmed mutations in cilia related genes, with and without DPMs, using the immunoperoxidase technique, and compared these to other syndromes with DPM. RESULTS: Acetylated tubulin expression was abnormal in DPM in SRP, Meckel syndrome, and autosomal recessive polycystic kidney disease (ARPKD), confirming ciliary anomalies. SDF-1 was abnormally expressed in SRP and two of three cases of autosomal dominant polycystic kidney disease (ADPKD) but not ARPKD or Meckel. Increased density of quiescent hepatic stellate cells was seen in SRP, Meckel, one of three cases of ARPKD, and two of three cases of ADPKD with aberrant hepatocyte expression of keratin 19 in SRP and ADPKD. Immunophenotypic abnormalities were present even in fetal liver without fully developed DPMs. The SRP case with DPM and pancreatic malformations showed abnormalities in the pancreatic head (influenced by mesenchyme from the septum transversum, similar to liver) but not pancreatic body (influenced by mesenchyme adjacent to the notochord). CONCLUSION: In SRP, there are differentiation defects of hepatocytes, cholangiocytes, and liver mesenchyme and, in rare cases, pancreatic mesenchymal anomalies. The morphological changes were subtle in early gestation but immunophenotypic abnormalities were present. Mesenchymal-epithelial interactions may contribute to the malformations. Birth Defects Research (Part A) 106:549-562, 2016. © 2016 Wiley Periodicals, Inc.


Assuntos
Feto , Fígado , Pâncreas , Síndrome de Costela Curta e Polidactilia , Feminino , Feto/anormalidades , Feto/embriologia , Humanos , Fígado/anormalidades , Fígado/embriologia , Masculino , Pâncreas/anormalidades , Pâncreas/embriologia , Síndrome de Costela Curta e Polidactilia/embriologia , Síndrome de Costela Curta e Polidactilia/patologia
18.
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
19.
Nat Commun ; 6: 7092, 2015 Jun 16.
Artigo em Inglês | MEDLINE | ID: mdl-26077881

RESUMO

The short rib polydactyly syndromes (SRPSs) are a heterogeneous group of autosomal recessive, perinatal lethal skeletal disorders characterized primarily by short, horizontal ribs, short limbs and polydactyly. Mutations in several genes affecting intraflagellar transport (IFT) cause SRPS but they do not account for all cases. Here we identify an additional SRPS gene and further unravel the functional basis for IFT. We perform whole-exome sequencing and identify mutations in a new disease-producing gene, cytoplasmic dynein-2 light intermediate chain 1, DYNC2LI1, segregating with disease in three families. Using primary fibroblasts, we show that DYNC2LI1 is essential for dynein-2 complex stability and that mutations in DYNC2LI1 result in variable length, including hyperelongated, cilia, Hedgehog pathway impairment and ciliary IFT accumulations. The findings in this study expand our understanding of SRPS locus heterogeneity and demonstrate the importance of DYNC2LI1 in dynein-2 complex stability, cilium function, Hedgehog regulation and skeletogenesis.


Assuntos
Cílios/metabolismo , Dineínas do Citoplasma/genética , Citoesqueleto/genética , Fibroblastos/metabolismo , Síndrome de Costela Curta e Polidactilia/genética , Transporte Biológico/genética , Feminino , Flagelos/metabolismo , Proteínas Hedgehog , Humanos , Masculino , Mutação , Linhagem
20.
Clin Chim Acta ; 447: 47-51, 2015 Jul 20.
Artigo em Inglês | MEDLINE | ID: mdl-25982780

RESUMO

A 26-year-old woman with a past history of fetal skeletal dysplasia was referred to our institution at 24weeks of gestation following a routine sonographic diagnosis of short limbs in the fetus. A fetal ultrasound showed short limbs, a narrow thorax, short ribs with marginal spurs, and polydactyly. Conventional cytogenetics analysis of cultured amniocytes demonstrated that the fetal karyotype was normal. Using targeted exome sequencing of 226 known genes implicated in inherited skeletal dysplasia, we identified compound heterozygous mutations in the DYNC2H1 gene in the fetus with short rib-polydactyly syndrome, type III (SRPS III), c.1151 C>T(p.Ala384Val) and c.4351 C>T (p.Gln1451*), which were inherited from paternally and maternally, respectively. These variants were further confirmed using Sanger sequencing and have not been previously reported. To our knowledge, this is the first report of DYNC2H1 mutations causing SRPS III, in the Chinese population. Our findings expand the number of reported cases of this rare disease, and indicate that targeted next-generation sequencing (NGS) is an accurate, rapid, and cost-effective method in the genetic diagnosis of fetal skeletal dysplasia.


Assuntos
Dineínas do Citoplasma/genética , Análise Mutacional de DNA , Feto/metabolismo , Heterozigoto , Sequenciamento de Nucleotídeos em Larga Escala , Síndrome de Costela Curta e Polidactilia/genética , Adulto , Sequência de Bases , Exoma/genética , Feminino , Humanos , Masculino , Linhagem , Gravidez , Diagnóstico Pré-Natal , Síndrome de Costela Curta e Polidactilia/diagnóstico por imagem , Ultrassonografia
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA