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1.
Am J Hum Genet ; 104(3): 439-453, 2019 Mar 07.
Artigo em Inglês | MEDLINE | ID: mdl-30773278

RESUMO

SPONASTRIME dysplasia is a rare, recessive skeletal dysplasia characterized by short stature, facial dysmorphism, and aberrant radiographic findings of the spine and long bone metaphysis. No causative genetic alterations for SPONASTRIME dysplasia have yet been determined. Using whole-exome sequencing (WES), we identified bi-allelic TONSL mutations in 10 of 13 individuals with SPONASTRIME dysplasia. TONSL is a multi-domain scaffold protein that interacts with DNA replication and repair factors and which plays critical roles in resistance to replication stress and the maintenance of genome integrity. We show here that cellular defects in dermal fibroblasts from affected individuals are complemented by the expression of wild-type TONSL. In addition, in vitro cell-based assays and in silico analyses of TONSL structure support the pathogenicity of those TONSL variants. Intriguingly, a knock-in (KI) Tonsl mouse model leads to embryonic lethality, implying the physiological importance of TONSL. Overall, these findings indicate that genetic variants resulting in reduced function of TONSL cause SPONASTRIME dysplasia and highlight the importance of TONSL in embryonic development and postnatal growth.

2.
Am J Med Genet A ; 176(8): 1784, 2018 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-30044529
3.
Mol Syndromol ; 9(2): 92-99, 2018 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-29593476

RESUMO

Mutations in the fibroblast growth factor receptor 3 gene (FGFR3) cause achondroplasia (ACH), hypochondroplasia (HCH), and thanatophoric dysplasia types I and II (TDI/TDII). In this study, we performed a genetic study of 123 Brazilian patients with these phenotypes. Mutation hotspots of the FGFR3 gene were PCR amplified and sequenced. All cases had recurrent mutations related to ACH, HCH, TDI or TDII, except for 2 patients. One of them had a classical TDI phenotype but a typical ACH mutation (c.1138G>A) in combination with a novel c.1130T>C mutation predicted as being pathogenic. The presence of the second c.1130T>C mutation likely explained the more severe phenotype. Another atypical patient presented with a compound phenotype that resulted from a combination of ACH and X-linked spondyloepiphyseal dysplasia tarda (OMIM 313400). Next-generation sequencing of this patient's DNA showed double heterozygosity for a typical de novo ACH c.1138G>A mutation and a maternally inherited TRAPPC2 c.6del mutation. All mutations were confirmed by Sanger sequencing. A pilot study using high-resolution melting (HRM) technique was also performed to confirm several mutations identified through sequencing. We concluded that for recurrent FGFR3 mutations, HRM can be used as a faster, reliable, and less expensive genotyping test than Sanger sequencing.

4.
Birth Defects Res ; 110(1): 72-80, 2018 01 15.
Artigo em Inglês | MEDLINE | ID: mdl-28949457

RESUMO

BACKGROUND: The World Health Organization has recognized the relevance of databases on craniofacial anomalies since . To date, there is no universal standard instrument/database focused on risk factors, clinical and genetic data collection, and follow-up that enables comparison between different populations and genotype-phenotype correlation. Although studies have shown that specific genes would impact outcomes, knowledge is not sufficient to subsidize cost-effectiveness strategies for diagnosis, surgical decision, and a multi-professional approach toward personalized medicine. METHODS: Based on a clinical genetic approach, a Web-based application named CranFlow-Craniofacial Anomalies: Registration, Flow, and Management has been developed. It prospectively collects clinical and genetic information for the Brazilian Database on Craniofacial Anomalies (syndromic and nonsyndromic orofacial cleft, 22q11.2 deletion syndrome, and other craniofacial related disorders). A comprehensive list of CranFlow's features is provided. RESULTS: We present preliminary results on 1546 cases already recorded and followed, which allows recognizing 10% of diagnosis changes. CONCLUSION: The identification of risk factors, consistent genetic approach associated with clinical data and follow-up result in valuable information to develop and improve personalized treatment and studies on genotype-phenotype correlation. Adoption of CranFlow in different clinical services may support comparison between populations. This application has the potential to contribute to improvements in healthcare, quality of services, clinical and surgical outcomes, and the standard of living of individuals with craniofacial anomalies. Birth Defects Research 110:72-80, 2018. © 2017 Wiley Periodicals, Inc.


Assuntos
Anormalidades Craniofaciais/classificação , Brasil/epidemiologia , Bases de Dados Factuais , Estudos de Associação Genética , Humanos , Sistema de Registros , Software
5.
Drug Discov Today ; 23(1): 187-195, 2018 01.
Artigo em Inglês | MEDLINE | ID: mdl-29129805

RESUMO

Rare genetic diseases collectively impact a significant portion of the world's population. For many diseases there is limited information available, and clinicians can find difficulty in differentiating between clinically similar conditions. This leads to problems in genetic counseling and patient treatment. The biomedical market is affected because pharmaceutical and biotechnology industries do not see advantages in addressing rare disease treatments, or because the cost of the treatments is too high. By contrast, technological advances including DNA sequencing and analysis, together with computer-aided tools and online resources, are allowing a more thorough understanding of rare disorders. Here, we discuss how the collection of various types of information together with the use of new technologies is facilitating diagnosis and, consequently, treatment of rare diseases.


Assuntos
Doenças Genéticas Inatas , Doenças Raras , Animais , Doenças Genéticas Inatas/diagnóstico , Doenças Genéticas Inatas/tratamento farmacológico , Doenças Genéticas Inatas/genética , Educação em Saúde , Pessoal de Saúde , Humanos , Participação do Paciente , Doenças Raras/diagnóstico , Doenças Raras/tratamento farmacológico , Doenças Raras/genética
6.
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
7.
Am J Med Genet A ; 173(4): 841-857, 2017 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-28328129

RESUMO

In October 2015, Zika virus (ZIKV) outbreak the Brazilian Ministry of Health (MoH). In response, the Brazilian Society of Medical Genetics established a task force (SBGM-ZETF) to study the phenotype of infants born with microcephaly due to ZIKV congenital infection and delineate the phenotypic spectrum of this newly recognized teratogen. This study was based on the clinical evaluation and neuroimaging of 83 infants born during the period from July, 2015 to March, 2016 and registered by the SBGM-ZETF. All 83 infants had significant findings on neuroimaging consistent with ZIKV congenital infection and 12 had confirmed ZIKV IgM in CSF. A recognizable phenotype of microcephaly, anomalies of the shape of skull and redundancy of the scalp consistent with the Fetal Brain Disruption Sequence (FBDS) was present in 70% of infants, but was most often subtle. In addition, features consistent with fetal immobility, ranging from dimples (30.1%), distal hand/finger contractures (20.5%), and feet malpositions (15.7%), to generalized arthrogryposis (9.6%), were present in these infants. Some cases had milder microcephaly or even a normal head circumference (HC), and other less distinctive findings. The detailed observation of the dysmorphic and neurologic features in these infants provides insight into the mechanisms and timings of the brain disruption and the sequence of developmental anomalies that may occur after prenatal infection by the ZIKV.


Assuntos
Surtos de Doenças , Doenças Fetais/epidemiologia , Microcefalia/epidemiologia , Complicações Infecciosas na Gravidez/epidemiologia , Infecção por Zika virus/epidemiologia , Anticorpos Antivirais/líquido cefalorraquidiano , Encéfalo/anormalidades , Encéfalo/virologia , Brasil/epidemiologia , Feminino , Doenças Fetais/diagnóstico por imagem , Doenças Fetais/patologia , Feto , Humanos , Imunoglobulina G/líquido cefalorraquidiano , Lactente , Microcefalia/complicações , Microcefalia/diagnóstico por imagem , Microcefalia/patologia , Neuroimagem , Gravidez , Complicações Infecciosas na Gravidez/diagnóstico , Complicações Infecciosas na Gravidez/patologia , Síndrome , Zika virus/crescimento & desenvolvimento , Zika virus/imunologia , Zika virus/patogenicidade , Infecção por Zika virus/complicações , Infecção por Zika virus/diagnóstico por imagem , Infecção por Zika virus/patologia
8.
Prenat Diagn ; 37(5): 435-439, 2017 May.
Artigo em Inglês | MEDLINE | ID: mdl-28207930

RESUMO

OBJECTIVE: The aim of this study was to quantify glycosaminoglycans (GAGs) in amniotic fluid (AF) from an MPS VII fetus compared with age-matched fetuses obtained from normal pregnancies. METHOD: Disaccharides were measured by liquid chromatography tandem mass spectrometry, compared to age-matched controls. Enzyme assay was performed in AF supernatant or cultured amniocytes. GUSB was analyzed by next generation sequencing using Ion Torrent Personal Genome Machine with a customized panel. RESULTS: No activity of ß-glucuronidase was detected in fetal cells. The pregnancy was spontaneously terminated in the third trimester. Genetic studies identified a homozygous mutation of p.N379D (c.1135A > G) in the GUSB gene. Liquid chromatography tandem mass spectrometry showed that chondroitin sulfate, dermatan sulfate, heparan sulfate, and keratan sulfate levels were markedly increased in the MPS VII AF, compared to those in age-matched control AF (dermatan sulfate, heparan sulfate, and chondroitin-6-sulfate more than 10 × than age-matched controls; chondroitin-4-sulfate and keratan sulfate more than 3 times higher). CONCLUSION: This is the first report of specific GAG analysis in AF from an MPS VII fetus, indicating that GAG elevation in AF occurs by 21 weeks of gestation and could be an additional tool for prenatal diagnosis of MPS VII and potentially other MPS types. © 2017 John Wiley & Sons, Ltd.


Assuntos
Líquido Amniótico/metabolismo , Doenças Fetais/metabolismo , Feto/metabolismo , Glicosaminoglicanos/metabolismo , Mucopolissacaridose VII/metabolismo , Adulto , Estudos de Casos e Controles , Feminino , Doenças Fetais/patologia , Feto/patologia , Humanos , Mucopolissacaridose VII/embriologia , Mucopolissacaridose VII/patologia , Gravidez , Regulação para Cima
10.
MMWR Morb Mortal Wkly Rep ; 65(3): 59-62, 2016 Jan 29.
Artigo em Inglês | MEDLINE | ID: mdl-26820244

RESUMO

In early 2015, an outbreak of Zika virus, a flavivirus transmitted by Aedes mosquitoes, was identified in northeast Brazil, an area where dengue virus was also circulating. By September, reports of an increase in the number of infants born with microcephaly in Zika virus-affected areas began to emerge, and Zika virus RNA was identified in the amniotic fluid of two women whose fetuses had been found to have microcephaly by prenatal ultrasound. The Brazil Ministry of Health (MoH) established a task force to investigate the possible association of microcephaly with Zika virus infection during pregnancy and a registry for incident microcephaly cases (head circumference ≥2 standard deviations [SD] below the mean for sex and gestational age at birth) and pregnancy outcomes among women suspected to have had Zika virus infection during pregnancy. Among a cohort of 35 infants with microcephaly born during August-October 2015 in eight of Brazil's 26 states and reported to the registry, the mothers of all 35 had lived in or visited Zika virus-affected areas during pregnancy, 25 (71%) infants had severe microcephaly (head circumference >3 SD below the mean for sex and gestational age), 17 (49%) had at least one neurologic abnormality, and among 27 infants who had neuroimaging studies, all had abnormalities. Tests for other congenital infections were negative. All infants had a lumbar puncture as part of the evaluation and cerebrospinal fluid (CSF) samples were sent to a reference laboratory in Brazil for Zika virus testing; results are not yet available. Further studies are needed to confirm the association of microcephaly with Zika virus infection during pregnancy and to understand any other adverse pregnancy outcomes associated with Zika virus infection. Pregnant women in Zika virus-affected areas should protect themselves from mosquito bites by using air conditioning, screens, or nets when indoors, wearing long sleeves and pants, using permethrin-treated clothing and gear, and using insect repellents when outdoors. Pregnant and lactating women can use all U.S. Environmental Protection Agency (EPA)-registered insect repellents according to the product label.


Assuntos
Microcefalia/epidemiologia , Microcefalia/virologia , Complicações Infecciosas na Gravidez/epidemiologia , Infecção por Zika virus/epidemiologia , Brasil/epidemiologia , Feminino , Humanos , Recém-Nascido , Gravidez
11.
Genet Mol Biol ; 38(1): 14-20, 2015 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-25983619

RESUMO

Campomelic dysplasia (CD) is an autosomal, dominantly inherited, skeletal abnormality belonging to the subgroup of bent bone dysplasias. In addition to bowed lower limbs, CD typically includes the following: disproportionate short stature, flat face, micrognathia, cleft palate, bell-shaped thorax, and club feet. Up to three quarters of 46, XY individuals may be sex-reversed. Radiological signs include scapular and pubic hypoplasia, narrow iliac wings, spaced ischia, and bowed femora and tibiae. Lethal CD is usually due to heterozygous mutations in SOX9, a major regulator of chondrocytic development. We present a detailed clinical and molecular characterization of nine Brazilian CD patients. Infants were either stillborn (n = 2) or died shortly after birth and presented similar phenotypes. Sex-reversal was observed in one of three chromosomally male patients. Sequencing of SOX9 revealed new heterozygous mutations in seven individuals. Six patients had mutations that resulted in premature transcriptional termination, while one infant had a single-nucleotide substitution at the conserved splice-site acceptor of intron 1. No clear genotype-phenotype correlations were observed. This study highlights the diversity of SOX9 mutations leading to lethal CD, and expands the group of known genetic alterations associated with this skeletal dysplasia.

13.
Am J Med Genet A ; 161A(12): 3078-86, 2013 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-24039125

RESUMO

Non-immune hydrops fetalis (NIHF) is a symptom caused by a heterogeneous group of conditions. Diagnostic investigations may constitute a real challenge. This study aimed to evaluate prospectively and systematically a series of NIHF cases using a research protocol expanded for studying inborn errors of metabolism (IEM) during 2 years-2010 and 2011. We also reviewed the frequency of IEM among the NIHF reported in literature. A clinical or etiopathogenic diagnosis was reached in 46 (86.8%) of the 53 studied cases. The main diagnostic groups were chromosomal anomalies (28.3%), syndromic (18.9%), isolated cardiovascular anomaly (7.5%) and congenital infection (7.5%). Metabolic causes were found in 5.7%, all lysosomal storage disorders (LSD). In seven (13.2%), no diagnosis was found in part because of incomplete evaluation. The hydrops was identified prenatally in 90.5% of cases. In 5.7% a spontaneous and complete resolution of the hydrops occurred during pregnancy. Overall mortality was 75.5%. The IEM frequency in the present study (5.7%) was higher than that usually reported. We suggest performing studies directed to IEMs if the more common causes are excluded.


Assuntos
Transtornos Cromossômicos/genética , Hidropisia Fetal/diagnóstico , Hidropisia Fetal/genética , Doenças por Armazenamento dos Lisossomos/genética , Adulto , Aberrações Cromossômicas , Transtornos Cromossômicos/complicações , Transtornos Cromossômicos/diagnóstico , Feminino , Humanos , Hidropisia Fetal/mortalidade , Hidropisia Fetal/fisiopatologia , Recém-Nascido , Doenças por Armazenamento dos Lisossomos/diagnóstico , Doenças por Armazenamento dos Lisossomos/fisiopatologia , Masculino , Erros Inatos do Metabolismo/diagnóstico , Erros Inatos do Metabolismo/genética , Gravidez
14.
Am J Hum Genet ; 92(1): 144-9, 2013 Jan 10.
Artigo em Inglês | MEDLINE | ID: mdl-23273569

RESUMO

Opsismodysplasia (OPS) is a severe autosomal-recessive chondrodysplasia characterized by pre- and postnatal micromelia with extremely short hands and feet. The main radiological features are severe platyspondyly, squared metacarpals, delayed skeletal ossification, and metaphyseal cupping. In order to identify mutations causing OPS, a total of 16 cases (7 terminated pregnancies and 9 postnatal cases) from 10 unrelated families were included in this study. We performed exome sequencing in three cases from three unrelated families and only one gene was found to harbor mutations in all three cases: inositol polyphosphate phosphatase-like 1 (INPPL1). Screening INPPL1 in the remaining cases identified a total of 12 distinct INPPL1 mutations in the 10 families, present at the homozygote state in 7 consanguinous families and at the compound heterozygote state in the 3 remaining families. Most mutations (6/12) resulted in premature stop codons, 2/12 were splice site, and 4/12 were missense mutations located in the catalytic domain, 5-phosphatase. INPPL1 belongs to the inositol-1,4,5-trisphosphate 5-phosphatase family, a family of signal-modulating enzymes that govern a plethora of cellular functions by regulating the levels of specific phosphoinositides. Our finding of INPPL1 mutations in OPS, a severe spondylodysplastic dysplasia with major growth plate disorganization, supports a key and specific role of this enzyme in endochondral ossification.


Assuntos
Exoma , Mutação , Osteocondrodisplasias/genética , Monoéster Fosfórico Hidrolases/genética , Adolescente , Adulto , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Recém-Nascido , Masculino , Fosfatidilinositol-3,4,5-Trifosfato 5-Fosfatases , Análise de Sequência de DNA/métodos , Adulto Jovem
15.
J Med Genet ; 49(4): 227-33, 2012 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-22499340

RESUMO

BACKGROUND: The lethal short rib polydactyly syndromes (SRP type I-IV) are characterised by notably short ribs, short limbs, polydactyly, multiple anomalies of major organs, and autosomal recessive mode of inheritance. Among them, SRP type II (Majewski; MIM 263520) is characterised by short ovoid tibiae or tibial agenesis and is radiographically closely related to SRP type IV (Beemer-Langer; MIM 269860) which is distinguished by bowed radii and ulnae and relatively well tubulated tibiae. NEK1 mutations have been recently identified in SRP type II. Double heterozygosity for mutations in both NEK1 and DYNC2H1 in one SRP type II case supported possible digenic diallelic inheritance. METHODS: The aim of this study was to screen DYNC2H1 and NEK1 in 13 SRP type II cases and seven SRP type IV cases. It was not possible to screen DYNC2H1 in two patients due to insufficient amount of DNA. RESULTS: The study identified homozygous NEK1 mutations in 5/13 SRP type II and compound heterozygous DYNC2H1 mutations in 4/12 cases. Finally, NEK1 and DYNC2H1 were excluded in 3/12 SRP type II and in all SRP type IV cases. The main difference between the mutation positive SRP type II group and the mutation negative SRP type II group was the presence of holoprosencephaly and polymycrogyria in the mutation negative group. CONCLUSION: This study confirms that NEK1 is one gene causing SRP type II but also reports mutations in DYNC2H1, expanding the phenotypic spectrum of DYNC2H1 mutations. The exclusion of NEK1 and DYNC2H1 in 3/12 SRP type II and in all SRP type IV cases further support genetic heterogeneity.


Assuntos
Proteínas de Ciclo Celular/genética , Dineínas do Citoplasma/genética , Proteínas Serina-Treonina Quinases/genética , Síndrome de Costela Curta e Polidactilia/genética , Consanguinidade , Feminino , Feto/anormalidades , Estudos de Associação Genética , Heterogeneidade Genética , Genótipo , Humanos , Masculino , Mutação , Quinase 1 Relacionada a NIMA , Gravidez
16.
Am J Med Genet A ; 158A(5): 1038-45, 2012 May.
Artigo em Inglês | MEDLINE | ID: mdl-22407836

RESUMO

Currently accepted birth prevalence for osteochondrodysplasias (OCD) of about 2/10,000 is based on few studies from small series of cases. We conducted a study based on more than 1.5 million births. OCD cases were detected from 1,544,496 births occurring and examined in 132 hospitals of ECLAMC (Latin American Collaborative Study of Congenital Malformations) between 2000 and 2007. Cases were detected and registered according to a pre-established protocol, and then ranked in four diagnostic evidence levels (DEL), according to available documentation. For the analysis of risk factors, a healthy control sample born in the same period was used. OCD was diagnosed in 492 newborns, resulting in a prevalence per 10,000 of 3.2 (95% CI: 2.9-3.5). Perinatal lethality (stillbirths plus early neonatal deaths) occurred in 50% of cases. Prenatal ultrasound diagnosis was made in 73% of cases (n = 359). Among 211 cases from the best documented group (DEL-1) and according to international classification, 33% of cases fit into the G-25 (osteogenesis imperfecta), 29% in Group-1 (FGFR3), and 8% in Group-18 (Bent bones). The prevalence of the main OCD types were: OI-0.74 (0.61-0.89); thanatophoric dysplasia-0.47 (0.36-0.59); and achondroplasia-0.44 (0.33-0.55). Paternal age (31.2 ± 8.5), parity (2.6), and parental consanguinity rate (5.4%) were higher in cases than in controls (P < 0.001). In conclusion, the OCD overall prevalence of 3.2 per 10,000 found seems to be more realistic than previous estimates. This study also confirmed the high perinatal mortality, and the association with high paternal age, parity, and parental consanguinity rate.


Assuntos
Osteocondrodisplasias/epidemiologia , Estudos de Casos e Controles , Consanguinidade , Humanos , Osteocondrodisplasias/diagnóstico , Osteocondrodisplasias/etiologia , Osteocondrodisplasias/mortalidade , Idade Paterna , Prevalência , Fatores de Risco , América do Sul/epidemiologia
17.
J Med Genet ; 48(2): 88-92, 2011 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-19648123

RESUMO

BACKGROUND: The lethal group of short-rib polydactyly (SRP) includes type I (Saldino-Noonan; MIM 263530), type II (Majewski; MIM 263520), type III (Verma-Naumoff; MIM 263510) and type IV (Beemer-Langer; MIM 269860). Jeune and Ellis-van Creveld dysplasias also used to be classified in the SRP group. Recently, mutations in a gene encoding a protein involved in intraflagellar transport, IFT80, have been identified in 3/39 patients with Jeune dysplasia but no extraskeletal manifestation. METHODS: Because of clinical and radiological similarities between Jeune dysplasia and the other lethal types of SRP, the authors decided to investigate IFT80 in a cohort of fetuses with the lethal forms of SRP (Majewski, Verma-Naumoff and Beemer-Langer) and antenatally diagnosed cases of Jeune dysplasia. Fifteen fetuses were identified. A double-molecular approach was adopted. For consanguineous families and for those with recurrent sibs, a haplotype analysis around the gene locus was first performed, and, for the others, all the coding exons of IFT80 were directly sequenced. RESULTS: Using the haplotype approach for two families, the authors excluded the IFT80 region as a candidate for them. Direct sequencing of IFT80 in the other 13 cases showed a G-to-C transversion in exon 8 (G241R) in only one SRP case closely related to the type III phenotype. CONCLUSIONS: The findings show that mutations in IFT80 can also be responsible for a lethal form of SRP and provide the molecular basis for the Jeune-Verma-Naumoff dysplasia spectrum.


Assuntos
Proteínas de Transporte/genética , Fenótipo , Sequência de Bases , Síndrome de Ellis-Van Creveld/genética , Síndrome de Ellis-Van Creveld/patologia , Feto , Marcadores Genéticos/genética , Haplótipos/genética , Humanos , Dados de Sequência Molecular , Linhagem , Polimorfismo de Nucleotídeo Único , Análise de Sequência de DNA , Síndrome de Costela Curta e Polidactilia/genética , Síndrome de Costela Curta e Polidactilia/patologia
18.
Am J Hum Genet ; 85(5): 706-10, 2009 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-19853239

RESUMO

Desbuquois dysplasia is a severe condition characterized by short stature, joint laxity, scoliosis, and advanced carpal ossification with a delta phalanx. Studying nine Desbuquois families, we identified seven distinct mutations in the Calcium-Activated Nucleotidase 1 gene (CANT1), which encodes a soluble UDP-preferring nucleotidase belonging to the apyrase family. Among the seven mutations, four were nonsense mutations (Del 5' UTR and exon 1, p.P245RfsX3, p.S303AfsX20, and p.W125X), and three were missense mutations (p.R300C, p.R300H, and p.P299L) responsible for the change of conserved amino acids located in the seventh nucleotidase conserved region (NRC). The arginine substitution at position 300 was identified in five out of nine families. The specific function of CANT1 is as yet unknown, but its substrates are involved in several major signaling functions, including Ca2+ release, through activation of pyrimidinergic signaling. Importantly, using RT-PCR analysis, we observed a specific expression in chondrocytes. We also found electron-dense material within distended rough endoplasmic reticulum in the fibroblasts of Desbuquois patients. Our findings demonstrate the specific involvement of a nucleotidase in the endochondral ossification process.


Assuntos
Doenças do Desenvolvimento Ósseo/genética , Cálcio/metabolismo , Mutação , Nucleotidases/genética , Regiões 5' não Traduzidas , Adolescente , Adulto , Sequência de Aminoácidos , Substituição de Aminoácidos , Arginina/metabolismo , Doenças do Desenvolvimento Ósseo/diagnóstico por imagem , Células Cultivadas , Pré-Escolar , Condrócitos/metabolismo , Cromossomos Humanos Par 17 , Códon sem Sentido , Consanguinidade , Retículo Endoplasmático Rugoso/ultraestrutura , Éxons , Evolução Fatal , Feminino , Fibroblastos/ultraestrutura , Homozigoto , Humanos , Lactente , Recém-Nascido , Masculino , Dados de Sequência Molecular , Mutação de Sentido Incorreto , Núcleo Familiar , RNA Mensageiro/metabolismo , Radiografia
19.
Trop Med Int Health ; 12(7): 833-7, 2007 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-17596249

RESUMO

OBJECTIVE: To investigate the association of Yellow Fever Vaccination (YFV) during pregnancy with the presence of structural defect in exposed babies. METHODS: An observed/expected frequencies study, before and after the vaccination campaign against YF was designed. 304 babies exposed to YFV during the prenatal period underwent dysmorphological examinations. The expected frequencies of malformations were obtained from a reference population of 10,691 births occurred in the period immediately prior to the vaccination campaign and born in the same region. These frequencies were evaluated using Poisson distribution model. RESULTS: The major malformation rate found in this study was 3.3% (CI 1.7-6.3%). Minor dysmorphisms, especially naevus, were significantly more frequent (P<0.001) than in the reference population. CONCLUSIONS: The data here presented provide no indication that immunization with YFV early in pregnancy increases the risk of major malformations. However, the association found between YFV during pregnancy and minor dysmorphisms, especially pigmented naevus, seems to be a bias of evaluation. We suggest, nevertheless, that a reproductive risk hypothesis regarding minor dysmorphisms should be considered in future studies involving YFV.


Assuntos
Anormalidades Induzidas por Medicamentos/etiologia , Vacina contra Febre Amarela/efeitos adversos , Anormalidades Induzidas por Medicamentos/epidemiologia , Anormalidades Múltiplas/induzido quimicamente , Anormalidades Múltiplas/epidemiologia , Adulto , Brasil/epidemiologia , Síndrome de Down/induzido quimicamente , Síndrome de Down/epidemiologia , Feminino , Humanos , Recém-Nascido , Cariotipagem , Masculino , Menstruação/fisiologia , Nevo/induzido quimicamente , Gravidez , Complicações Infecciosas na Gravidez/prevenção & controle , Resultado da Gravidez , Prevalência , Fatores de Risco , Febre Amarela/prevenção & controle
20.
Cleft Palate Craniofac J ; 43(2): 148-51, 2006 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-16526918

RESUMO

OBJECTIVE: Screen the known craniosynostotic related gene, FGFR1 (exon 7), and two new identified potential candidates, CER1 and CDON, in patients with syndromic and nonsyndromic metopic craniosynostosis to determine if they might be causative genes. DESIGN: Using single-strand conformational polymorphisms (SSCPs), denaturing high-performance liquid chromatography, and/or direct sequencing, we analyzed a total of 81 patients for FGFR1 (exon 7), 70 for CER1, and 44 for CDON. PATIENTS: Patients were ascertained in the Centro de Estudos do Genoma Humano in São Paulo, Brazil (n = 39), the Craniofacial Unit, Oxford, U.K. (n = 23), and the Johns Hopkins University, Baltimore, Maryland (n = 31). Clinical inclusion criteria included a triangular head and/or forehead, with or without a metopic ridge, and a radiographic documentation of metopic synostosis. Both syndromic and nonsyndromic patients were studied. RESULTS: No sequence alterations were found for FGFR1 (exon 7). Different patterns of SSCP migration for CER1 compatible with the segregation of single nucleotide polymorphisms reported in the region were identified. Seventeen sequence alterations were detected in the coding region of CDON, seven of which are new, but segregation analysis in parents and homology studies did not indicate a pathological role. CONCLUSIONS: FGFR1 (exon 7), CER1, and CDON are not related to trigonocephaly in our sample and should not be considered as causative genes for metopic synostosis. Screening of FGFR1 (exon 7) for diagnostic purposes should not be performed in trigonocephalic patients.


Assuntos
Moléculas de Adesão Celular/genética , Craniossinostoses/genética , Glicoproteínas de Membrana/genética , Proteínas/genética , Receptor Tipo 1 de Fator de Crescimento de Fibroblastos/genética , Proteínas Supressoras de Tumor/genética , Craniossinostoses/diagnóstico por imagem , Análise Mutacional de DNA/métodos , Éxons/genética , Humanos , Peptídeos e Proteínas de Sinalização Intercelular , Polimorfismo Conformacional de Fita Simples , Radiografia , Síndrome , Proteínas de Xenopus
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