RESUMO
Congenital hypothyroidism with biallelic thyroglobulin (Tg protein, encoded by the TG gene) mutation is an endoplasmic reticulum (ER) storage disease. Many patients (and animal models) grow an enlarged thyroid (goiter), yet some do not. In adulthood, hypothyroid TGcog/cog mice (bearing a Tg-L2263P mutation) exhibit a large goiter, whereas adult WIC rats bearing the TGrdw/rdw mutation (Tg-G2298R) exhibit a hypoplastic thyroid. Homozygous TG mutation has been linked to thyroid cell death, and cytotoxicity of the Tg-G2298R protein was previously thought to explain the lack of goiter in WIC-TGrdw/rdw rats. However, recent studies revealed that TGcog/cog mice also exhibit widespread ER stress-mediated thyrocyte death, yet under continuous feedback stimulation, thyroid cells proliferate in excess of their demise. Here, to examine the relative proteotoxicity of the Tg-G2298R protein, we have used CRISPR-CRISPR-associated protein 9 technology to generate homozygous TGrdw/rdw knock-in mice in a strain background identical to that of TGcog/cog mice. TGrdw/rdw mice exhibit similar phenotypes of defective Tg protein folding, thyroid histological abnormalities, hypothyroidism, and growth retardation. TGrdw/rdw mice do not show evidence of greater ER stress response or stress-mediated cell death than TGcog/cog mice, and both mouse models exhibit sustained thyrocyte proliferation, with comparable goiter growth. In contrast, in WIC-TGrdw/rdw rats, as a function of aging, the thyrocyte proliferation rate declines precipitously. We conclude that the mutant Tg-G2298R protein is not intrinsically more proteotoxic than Tg-L2263P; rather, aging-dependent difference in maintenance of cell proliferation is the limiting factor, which accounts for the absence of goiter in adult WIC-TGrdw/rdw rats.
Assuntos
Bócio , Hipotireoidismo , Tireoglobulina , Glândula Tireoide , Animais , Proliferação de Células , Bócio/congênito , Bócio/genética , Bócio/metabolismo , Hipotireoidismo/genética , Hipotireoidismo/metabolismo , Camundongos , Ratos , Tireoglobulina/genética , Glândula Tireoide/fisiopatologiaRESUMO
Na+ /I- symporter (NIS) transports iodide into thyrocytes, a fundamental step for thyroid hormone biosynthesis. Our aim was to evaluate NIS regulation in different status of goitrogenesis and its underlying mechanisms. Wistar rats were treated with methimazole (MMI) for 5 and 21 days, to achieve different status of goiter. We then evaluated the effect of MMI removal for 1 day (R1d), after 5 (R1d-5d) or 21 (R1d-21d) days of MMI treatment. MMI increased thyroid weight, iodide uptake and in vitro TPO activity in a time-dependent way. Although MMI removal evoked a rapid normalization of TPO activity in R1d-5d, it was still high in R1d-21d. On the other hand, iodide uptake was rapidly down-regulated in R1d-21d, but not in R1d-5d, suggesting that the increased TPO activity in R1d-21d led to increased intraglandular organified iodine (I-X), which is known to inhibit iodide uptake. Since TGFß has been shown to mediate some effects of I-X, we evaluated TGFß and TGFß receptor mRNA levels, which were increased in R1d-21d. Moreover, it has been demonstrated that TGFß stimulates NOX4. Accordingly, our data revealed increased NOX4 expression and H2 O2 generation in R1d-21d. Finally, we evaluated the effect of H2 O2 on NIS function and mRNA levels in PCCL3 thyroid cell line, which were reduced. Thus, the present study suggests that there is a relationship between the size of the goiter and NIS regulation and that the mechanism might involve I-X, TGFß, NOX4 and increased ROS production.
Assuntos
Bócio/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Simportadores/metabolismo , Glândula Tireoide/metabolismo , Animais , Transporte Biológico , Regulação da Expressão Gênica , Bócio/genética , Peróxido de Hidrogênio/metabolismo , Iodetos/metabolismo , NADPH Oxidase 4/genética , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Ratos , Ratos Wistar , Fator de Crescimento Transformador beta1/genéticaRESUMO
The pathogenesis of diffuse toxic goiter has not yet been fully understood. The literature increasing commonly focusses on the issues related to the processes occurring in the thyroid gland itself: proliferation, apoptosis, and angiogenesis. AIM: to investigate clinical and laboratory parameters, as well as the expression of Ki-67, Bcl-2, Bax, Fas-L, CD34, VEGF, and FGF proteins in various postoperative outcomes of patients operated on for diffuse toxic goiter. SUBJECTS AND METHODS: The investigation enrolled 24 women who had undergone surgery using the technique described by E.S. Drachinskaya. Immunohistochemical tests were carried out according to the standard protocol. The expression of Ki-67, Bcl-2, Bax, Fas-L, CD 34, VEGF, angiopoietin, and FGF proteins was determined. RESULTS: The patients with postoperative thyrotoxicosis were ascertained to have a significantly greater expression of anti-apoptotic protein Bcl-2, proliferation marker Ki-67, vascular factors (FGF, VEGF), and CD 34. CONCLUSION: The relative expression area of the anti-apoptotic protein Bcl-2 of more than 2.19 or the proliferation protein Ki-67 of more than 1.059 was found to predict the development of postoperative thyrotoxicosis with an accuracy of higher than 85%.
Assuntos
Biomarcadores , Proliferação de Células/genética , Bócio/genética , Neovascularização Patológica/genética , Adulto , Antígenos CD34/genética , Apoptose/genética , Proteína Ligante Fas/genética , Feminino , Bócio/patologia , Bócio/cirurgia , Humanos , Antígeno Ki-67/genética , Pessoa de Meia-Idade , Proteínas Proto-Oncogênicas c-bcl-2/genética , Glândula Tireoide/patologia , Proteína X Associada a bcl-2/genéticaRESUMO
BACKGROUND: Pendred syndrome is a rare autosomal recessive condition, characterized by functional impairment of thyroid gland and sensorineural hearing loss. The syndrome presents in patients with homozygous or compound heterozygous mutation. The presentation in the form of neck mass in a newborn is rare. CASE CHARACTERISTICS: A 1 month old baby presented to us with neck mass, which was found to be an enlarged thyroid gland. Thyroid function tests were consistent with hypothyroidism. Further evaluation revealed moderate sensorineural hearing loss; genetic analysis showed that baby was homozygous for the known mutations causing the disease. INTERVENTION: Thyroid hormone replacement and hearing habilitation were done. Follow up showed regression of the neck mass and normalization of thyroid function tests. Genetic counseling of the family was done. MESSAGE: Identification of the exact cause of congenital hypothyroidism can prevent grave consequences later on for the patient as well as for the family.
Assuntos
Hipotireoidismo Congênito/diagnóstico , Bócio Nodular/diagnóstico , Bócio/diagnóstico , Perda Auditiva Neurossensorial/diagnóstico , Hipotireoidismo Congênito/genética , Bócio/congênito , Bócio/genética , Bócio Nodular/congênito , Bócio Nodular/genética , Perda Auditiva Neurossensorial/congênito , Perda Auditiva Neurossensorial/genética , Humanos , Recém-Nascido , Mutação , Testes de Função TireóideaRESUMO
The syndrome of inappropriate secretion of thyrotropin (SITSH) is a hallmark of resistance to thyroid hormone (RTH) due to mutations in the ß isoform of the thyroid hormone receptor (TRß). Here, we report on a family of RTH due to a TRß mutation (RTHß) and presenting occasional SITSH. The proband was a 16 year-old girl with a goiter, detected at a school physical examination. She was initially diagnosed as having euthyroid Hashimoto thyroiditis because her thyroid function was normal with a positive anti-thyroglobulin antibody. Follow-up examinations resulted in mild SITSH on some occasions and euthyroid on the other occasions. A magnetic resonance imaging (MRI) revealed a normal pituitary gland. Because her mother also had mild SITSH, genetic analysis was performed and revealed a heterozygous point mutation in TRß (p.R316C). Previously, the p.R316C had only been found in severe RTH cases with homozygous mutations or with an ectopic thyroid. Her mother with a heterozygous mutation showed variable RTH phenotype on T3 suppression testing. In conclusion, the prevalence of RTHß might be underestimated and occasional SITSH could also suggest RTHß. TRß gene mutation is not always correlated with the RTH phenotype.
Assuntos
Bócio/genética , Mutação , Receptores beta dos Hormônios Tireóideos/genética , Síndrome da Resistência aos Hormônios Tireóideos/genética , Tireotropina/metabolismo , Adolescente , Feminino , HumanosRESUMO
The history of human genetics has been a neglected topic in history of science and medicine for a long time. Only recently, have medical historians begun to pay more attention to the history of human heredity. An important research question deals with the interconnections between human genetics and eugenics. This paper addresses this question: By focusing on a Swiss case study, the investigation of the heredity of goiter, I will argue that there existed close but also ambiguous relations between heredity research and eugenics in the twentieth century. Studies on human heredity often produced evidence that challenged eugenic aims and ideas. Concurrently, however, these studies fostered visions of genetic improvement of human populations.
Assuntos
Eugenia (Ciência)/história , Genética Médica/história , Bócio/genética , Bócio/história , Socialismo Nacional/história , Alemanha , História do Século XIX , História do Século XX , Humanos , SuíçaRESUMO
Thyroid disorders such as goiters represent important diseases, especially in iodine-deficient areas. Sibling studies have demonstrated that genetic factors substantially contribute to the interindividual variation of thyroid volume. We performed a genome-wide association study of this phenotype by analyzing a discovery cohort consisting of 3620 participants of the Study of Health in Pomerania (SHIP). Four genetic loci were associated with thyroid volume on a genome-wide level of significance. Of these, two independent loci are located upstream of and within CAPZB, which encodes the ß subunit of the barbed-end F-actin binding protein that modulates actin polymerization, a process crucial in the colloid engulfment during thyroglobulin mobilization in the thyroid. The third locus marks FGF7, which encodes fibroblast growth factor 7. Members of this protein family have been discussed as putative signal molecules involved in the regulation of thyroid development. The fourth locus represents a "gene desert" on chromosome 16q23, located directly downstream of the predicted coding sequence LOC440389, which, however, had already been removed from the NCBI database as a result of the standard genome annotation processing at the time that this study was initiated. Experimental proof of the formerly predicted mature mRNA, however, demonstrates that LOC440389 indeed represents a real gene. All four associations were replicated in an independent sample of 1290 participants of the KORA study. These results increase the knowledge about genetic factors and physiological mechanisms influencing thyroid volume.
Assuntos
Loci Gênicos , Estudo de Associação Genômica Ampla , Bócio/genética , Glândula Tireoide/patologia , Actinas/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Bócio/patologia , Humanos , Masculino , Pessoa de Meia-Idade , Tamanho do Órgão , Fenótipo , Polimerização , Polimorfismo de Nucleotídeo Único , Fatores de Risco , Adulto JovemRESUMO
OBJECTIVE: The aim of this study was to screen for DUOX2, TPO and TG mutations in Chinese patients with congenital hypothyroidism (CH) and goitre and to define the relationships between DUOX2 genotypes and clinical phenotypes. METHODS: Blood samples were collected from 67 patients with CH and goitre in Shandong Province, China. Genomic DNA was extracted from peripheral blood leucocytes. PCR and direct sequencing were used to analyse all exons of DUOX2, TPO and TG. Detailed medical records were then collected, and the relationship between DUOX2 genotype and the clinical phenotype of CH and goitre caused by DUOX2 mutations was investigated. RESULTS: Analysis of DUOX2 revealed nine mutations, including one novel nonsense mutation (p.W734X), six novel missense mutations (p.N100D, p.S660L, p.A1131S, p.W1181G, p.A1206T and p.R1267W) and two recurrent mutations (p.R701X and p.R1110Q) in 10 patients from 10 unrelated families. Monoallelic and compound heterozygous mutations in DUOX2 were associated with permanent or transient CH. No mutation was found after screening all exons of TPO and TG. CONCLUSION: Our study identified DUOX2 mutations in 14·9% of Chinese patients investigated with CH and goitre. Because the relationships between DUOX2 genotypes and clinical phenotypes are extremely complex, however, further studies are needed to identify more mutations in known genes which are involved in CH and goitre.
Assuntos
Hipotireoidismo Congênito/genética , Bócio/genética , NADPH Oxidases/genética , Autoantígenos/genética , Criança , Pré-Escolar , Hipotireoidismo Congênito/etiologia , Oxidases Duais , Feminino , Genótipo , Humanos , Lactente , Iodeto Peroxidase/genética , Proteínas de Ligação ao Ferro/genética , Masculino , Mutação , Fenótipo , Tireoglobulina/genéticaRESUMO
Outbred stocks of rats have been used extensively in biomedical, pharmaceutical and/or toxicological studies as a model of genetically heterogeneous human populations. One of such stocks is the Wistar Hannover GALAS rat. However, the colony of Wistar Hannover GALAS rat has been suspected of keeping a problematic mutation that manifests two distinct spontaneous abnormalities, goiter and dwarfism, which often confuses study results. We have successfully identified the responsible mutation, a guanine to thymine transversion at the acceptor site (3' end) of intron 6 in the thyroglobulin (Tg) gene (Tgc.749-1G>T), that induces a complete missing of exon 7 from the whole Tg transcript by mating experiments and subsequent molecular analyses. The following observations confirmed that Tgc.749-1G>T/Tgc.749-1G>T homozygotes manifested both dwarfism and goiter, while Tgc.749-1G>T/+ heterozygotes had only a goiter with normal appearance, suggesting that the mutant phenotypes inherit as an autosomal semi-dominant trait. The mutant phenotypes, goiter and dwarfism, mimicked those caused by typical endocrine disrupters attacking the thyroid. Hence a simple and reliable diagnostic methodology has been developed for genomic DNA-based genotyping of animals. The diagnostic methodology reported here would allow users of Wistar Hannover GALAS rats to evaluate their study results precisely by carefully interpreting the data obtained from Tgc.749-1G>T/+ heterozygotes having externally undetectable thyroidal lesions.
Assuntos
Nanismo/genética , Bócio/genética , Mutação , Splicing de RNA , Tireoglobulina/genética , Animais , Animais não Endogâmicos , Sequência de Bases , Dicofol/toxicidade , Nanismo/metabolismo , Nanismo/patologia , Disruptores Endócrinos/toxicidade , Éxons , Feminino , Expressão Gênica , Bócio/metabolismo , Bócio/patologia , Heterozigoto , Homozigoto , Íntrons , Masculino , Dados de Sequência Molecular , Ratos , Ratos Wistar , Tireoglobulina/metabolismo , Glândula Tireoide/efeitos dos fármacos , Glândula Tireoide/metabolismo , Glândula Tireoide/patologiaAssuntos
Hipotireoidismo Congênito/diagnóstico , Bócio/diagnóstico , Glândula Tireoide/metabolismo , Tireoidectomia , Criança , Hipotireoidismo Congênito/patologia , Hipotireoidismo Congênito/cirurgia , Bócio/genética , Bócio/patologia , Bócio/cirurgia , Humanos , Masculino , Glândula Tireoide/patologia , Glândula Tireoide/cirurgia , Hormônios Tireóideos/genéticaRESUMO
Iodine deficiency-induced goiter continues to be a global public health concern, with varying manifestations based on geography, patient's age, and sex. To gain insights into clinical occurrences, a retrospective study analyzed medical records from patients with iodine deficiency-induced goiter or thyroid cancer who underwent surgery at the Community Hospital in Riehen, Switzerland, between 1929 and 1989. Despite today's adequate iodine supplementation, a significant risk for iodine-independent goiter remains in Switzerland, suggesting that genetic factors, among others, might be involved. Thus, a pilot study exploring the feasibility of genetic analysis of blood spots from these medical records was conducted to investigate and enhance the understanding of goiter development, potentially identify genetic variations, and explore the influence of dietary habits and other environmental stimuli on the disease.Blood prints from goiter patients' enlarged organs were collected per decade from medical records. These prints had been made by pressing, drawing, or tracing (i.e., pressed and drawn) the removed organs onto paper sheets. DNA analysis revealed that its yields varied more between the prints than between years. A considerable proportion of the samples exhibited substantial DNA degradation unrelated to sample collection time and DNA mixtures of different contributors. Thus, each goiter imprint must be individually evaluated and cannot be used to predict the success rate of genetic analysis in general. Collecting a large sample or the entire blood ablation for genetic analysis is recommended to mitigate potential insufficient DNA quantities. Researchers should also consider degradation and external biological compounds' impact on the genetic analysis of interest, with the dominant contributor anticipated to originate from the patient's blood.
Assuntos
Bócio , Iodo , Neoplasias da Glândula Tireoide , Humanos , Suíça , Neoplasias da Glândula Tireoide/genética , Neoplasias da Glândula Tireoide/sangue , Bócio/genética , Bócio/sangue , Iodo/deficiência , Masculino , Feminino , Alemanha , História do Século XX , Estudos Retrospectivos , Pessoa de Meia-Idade , AdultoRESUMO
BACKGROUND: In this study, we used targeted next-generation sequencing (NGS) to investigate the genetic basis of congenital hypothyroidism (CH) in a 19-year-old Tunisian man who presented with severe hypothyroidism and goiter. CASE PRESENTATION: The propositus reported the appearance of goiter when he was 18. Importantly, he did not show signs of mental retardation, and his growth was proportionate. A partial organification defect was detected through the perchlorate-induced iodide discharge test. NGS identified a novel homozygous mutation in exon 18 of the SLC26A7 gene (P628Qfs*11), which encodes for a new iodide transporter. This variant is predicted to result in a truncated protein. Notably, the patient's euthyroid brother was heterozygous for the same mutation. No renal acid-base abnormalities were found and the administration of 1 mg of iodine failed to correct hypothyroidism. CONCLUSIONS: We described the first case of goitrous CH due to a homozygous mutation of the SLC26A7 gene diagnosed during late adolescence.
Assuntos
Hipotireoidismo Congênito , Homozigoto , Mutação , Transportadores de Sulfato , Humanos , Masculino , Antiporters , Hipotireoidismo Congênito/genética , Hipotireoidismo Congênito/diagnóstico , Bócio/genética , Transportadores de Sulfato/genética , AdolescenteRESUMO
Biallelic loss-of-function variants in the IYD gene cause hypothyroidism resulting from iodine wasting. We describe 8 patients (from 4 families in which the parents are first cousins) who are homozygous for a variant in IYD (including a novel missense deleterious variant, c.791C>T [P264L], in 1 family). Seven patients presented between 5 and 16 years of age with a large goiter, overt hypothyroidism, and a high serum thyroglobulin. The goiter subsided with levothyroxine therapy in most. Upon stopping levothyroxine in 5 patients, goiter and hypothyroidism reappeared in 3. In these 3 patients, a rising serum thyroglobulin concentration preceded hypothyroidism and goiter and urinary iodine excretion was low. In patients who remained euthyroid, urinary iodine was normal. In conclusion, these patients bearing biallelic pathogenic variants in IYD developed a large goiter, a high serum thyroglobulin, and overt hypothyroidism when their iodine intake was low.
Assuntos
Bócio , Hipotireoidismo , Linhagem , Tiroxina , Humanos , Feminino , Masculino , Adolescente , Hipotireoidismo/genética , Criança , Pré-Escolar , Tiroxina/uso terapêutico , Bócio/genética , Tireoglobulina/genética , Iodo/deficiência , Alelos , Mutação de Sentido Incorreto , SimportadoresRESUMO
Congenital hypothyroidism with goiter (CHG) occurring as an autosomal recessive disorder is typically due to a defect of thyroid hormone synthesis (aka dyshormonogenesis). Thyroid peroxidase (TPO) is a multifunctional, heme-containing enzyme whose activity is required, and several inactivating TPO mutations causing CHG in humans and dogs have been described. Recently, two half-sib Spanish water dog (SWD) pups were diagnosed with CHG based on clinical signs, endocrine testing, and thyroid histology. TPO enzyme activity was absent, and immuno-cross-reactive TPO was undetectable in affected-dog thyroid tissue. A single guanosine insertion was observed in the first exon of the affected-dog TPO cDNA at a site not previously thought to be within the coding sequence. The insertion allele segregated with the deduced disease allele in the SWD breed and was not observed in unrelated dogs of various breeds. Comparison of the insertion site (an 8-nt poly-G tract) with the orthologous sequences of other mammalian reference genomes revealed that the octa-G tract obliterated the intron 1 splice acceptor site and the exon 2 translation initiation codon found at that position in other species. An in-frame ATG in strong Kozak consensus context was observed in the normal dog sequence 12 codons 5' of the usual mammalian start site, suggesting that dogs have lost the noncoding exon 1 demonstrated in human and mouse. A survey of TPO sequences in other carnivore species indicates that the poly-G tract necessitating an alternative translation initiation site is a canid-specific feature.
Assuntos
Cães/genética , Iodeto Peroxidase/química , Iodeto Peroxidase/genética , Alelos , Animais , Sequência de Bases , Hipotireoidismo Congênito/genética , Hipotireoidismo Congênito/patologia , DNA Complementar/genética , DNA Complementar/isolamento & purificação , Evolução Molecular , Éxons , Bócio/congênito , Bócio/genética , Bócio/patologia , Dados de Sequência Molecular , Mutação , Fenótipo , Análise de Sequência de DNA , Especificidade da Espécie , Hormônios Tireóideos/sangueRESUMO
BACKGROUND: Pendred syndrome is a common autosomal recessive disorder causing deafness. Features include sensorineural hearing impairment, goitre, enlarged vestibular aqueducts (EVA) and occasionally Mondini dysplasia. Hearing impairment and EVA may occur in the absence of goitre or thyroid dyshormonogensis in a condition known as non-syndromic EVA. A significant number of patients with Pendred syndrome and non-syndromic EVA show only one mutation in SLC26A4. Two genes, KCNJ10, encoding an inwardly rectifying potassium channel and FOXI1, a transcriptional factor gene, are thought to play a role in the disease phenotypes. METHODS: Using Polymerase Chain Reaction and Sanger sequencing, sixty-eight patients with monoallelic mutations of SLC26A4 were tested for mutations in KCNJ10 and FOXI1. RESULTS: Two variants were observed in the KCNJ10 gene, p.Arg271Cys in three patients and p.Arg18Gln in one patient; only one variant, p.Arg123Trp was observed in the FOXI1 gene in a single patient. Both p.Arg271Cys and p.Arg18Gln are likely to be polymorphisms as judged by their frequency in the general population. CONCLUSION: Therefore we found no evidence for a significant association between mutations of KCNJ10 and FOXI1 with SLC26A4. It was also observed that the variant, p.Arg271Cys in KCNJ10, previously thought to have a protective effect against seizure susceptibility, was found in a patient with Pendred syndrome with co-existing epilepsy.
Assuntos
Fatores de Transcrição Forkhead/genética , Bócio Nodular/genética , Perda Auditiva Neurossensorial/genética , Proteínas de Membrana Transportadoras/genética , Mutação , Canais de Potássio Corretores do Fluxo de Internalização/genética , Aqueduto Vestibular/patologia , Alelos , Predisposição Genética para Doença , Genótipo , Bócio/genética , Humanos , Fenótipo , Reação em Cadeia da Polimerase , Análise de Sequência de DNA , Transportadores de SulfatoRESUMO
Familial goiter is a genetic disease showing heterogeneous expression. To identify causative genes, we investigated three multigenerational goiter families with an autosomal dominant inheritance pattern. We performed genome-wide linkage analysis on all the families, combined with whole-exome sequencing in two affected individuals from each family. For linkage analysis, we considered loci with logarithm of odds (LOD) scores >1.5 as candidate regions for identification of rare variants. In one of the families, we found two rare heterozygous missense variants, p.V56M in RGS12 and p.G37D in GRPEL1, which segregate with goiter and are both located within the same haplotype on 4p16. This haplotype was not observed in 150 controls. In the other two families, we identified two additional rare missense variants segregating with goiter, p.A551T in CLIC6 on 21q22.12 and p.V412A in WFS1 on 4p16. In controls, the minor allele frequency (MAF) of p.V412A in WFS1 was 0.017 while p.A551T in CLIC6 was not detected. All identified genes (RGS12, GRPEL1, CLIC6 and WFS1) show expression in the human thyroid gland, suggesting that they may play a role in thyroid gland function. Moreover, these four genes are novel with regard to their involvement in familial goiter, supporting genetic heterogeneity of this disease.
Assuntos
Exoma , Ligação Genética , Bócio/genética , Análise de Sequência de DNA/métodos , Sequência de Aminoácidos , Povo Asiático/genética , Estudos de Casos e Controles , Clonagem Molecular , Hipotireoidismo Congênito/genética , Bases de Dados Genéticas , Feminino , Frequência do Gene , Heterogeneidade Genética , Predisposição Genética para Doença , Genoma Humano , Estudo de Associação Genômica Ampla , Haplótipos , Humanos , Japão , Masculino , Dados de Sequência Molecular , Linhagem , Polimorfismo de Nucleotídeo Único , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Alinhamento de SequênciaRESUMO
Inherited causes account for about 50% of individuals presenting with childhood (prelingual) hearing loss, of which 70% are due to mutation in numerous single genes which impair auditory function alone (non-syndromic). The remainder are associated with other developmental anomalies termed syndromic deafness. Genes responsible for syndromic forms of hearing loss include the COL4A5 gene in Alport syndrome and the PAX3 and MITF genes in Waardenburg syndrome. Pendred syndrome is an autosomal recessive disorder associated with developmental abnormalities of the cochlea, sensorineural hearing loss and diffuse thyroid enlargement (goitre). Pendred syndrome is the most common syndromal form of deafness, yet the primary defect remains unknown. We have established a panel of 12 families with two or more affected individuals and used them to search for the location of the Pendred gene by linkage analysis. We excluded localization to four previously mapped nonsyndromic deafness loci but obtained conclusive evidence for linkage of the Pendred syndrome gene to microsatellite markers on chromosome 7q31 (D7S495 Zmax 7.32, Qmax = 0). This region contains a gene, DFNBL, for autosomal recessive non-syndromic sensorineural hearing loss. Multipoint analysis indicates that DFNB4 and Pendred syndrome co-localize to the same 5.5 centiMorgan (cM) interval flanked by D7S501 and D7S523. These data raise the possibility that Pendred syndrome is either allelic with DFNB4 or may represent an inherited contiguous gene disorder, not clinically manifest in the heterozygote.
Assuntos
Cromossomos Humanos Par 7/genética , Bócio/genética , Perda Auditiva Neurossensorial/genética , Mapeamento Cromossômico , Feminino , Genes Recessivos , Ligação Genética , Humanos , Masculino , Repetições de Microssatélites , Linhagem , SíndromeRESUMO
Exactly 100 years ago, in 1896, Pendred first described the association of congenital deafness with thyroid goitre (MM#274600). The incidence of Pendred syndrome is estimated at 7.5-10/100,000, and may be responsible for as much as 10% of hereditary deafness. The cause of the congenital deafness in Pendred syndrome is obscure, although a Mondini type malformation of the cochlea exists in some patients. The reason for the association between the thyroid and cochlear defects is similarly obscure, leading some investigators to suggest that the two recessive defects may be occurring together by chance in highly consanguineous families. An in vivo defect in thyroid iodine organification in Pendred syndrome patients has been reported. However, the molecular basis of this defect is unknown and the presence of an intrinsic thyroidal defect has not been conclusively demonstrated. We have adopted a genetic linkage study as a first step towards identifying the gene. The availability of an inbred Pendred syndrome kindred allowed us to utilize an efficient DNA pooling strategy to perform a genome-wide linkage search for the disease locus. In this way, we have mapped the disease locus to an approximately 9-cM interval between GATA23F5 and D7S687 on chromosome 7. In addition, we demonstrate an intrinsic thyroid iodine organification defect in a patient's thyroid cells as the cause of the thyroid dysfunction.
Assuntos
Cromossomos Humanos Par 7/genética , Surdez/genética , Bócio/genética , Iodo/metabolismo , Glândula Tireoide/metabolismo , Mapeamento Cromossômico , Surdez/congênito , Surdez/etiologia , Feminino , Ligação Genética , Marcadores Genéticos , Bócio/etiologia , Humanos , Técnicas In Vitro , Iodeto Peroxidase/genética , Masculino , Linhagem , Síndrome , Tireoglobulina/genéticaRESUMO
Pendred syndrome is the most common form of syndromic deafness and characterized by congenital sensorineural hearing loss and goitre. This disorder was mapped to chromosome 7 and the gene causing Pendred syndrome (PDS) was subsequently identified by positional cloning. PDS encodes a putative transmembrane protein designated pendrin. Pendrin is closely related to a family of sulfate transport proteins that includes the rat sulfate-anion transporter (encoded by Sat-1; 29% amino acid sequence identity), the human diastrophic dysplasia sulfate transporter (encoded by DTD; 32%) and the human sulfate transporter 'downregulated in adenoma' (encoded by DRA; 45%). On the basis of this homology and the presence of a slightly modified sulfate-transporter signature sequence comprising its putative second transmembrane domain, pendrin has been proposed to function as a sulfate transporter. We were unable to detect evidence of sulfate transport following the expression of pendrin in Xenopus laevis oocytes by microinjection of PDS cRNA or in Sf9 cells following infection with PDS-recombinant baculovirus. The rates of transport for iodide and chloride were significantly increased following the expression of pendrin in both cell systems. Our results demonstrate that pendrin functions as a transporter of chloride and iodide, but not sulfate, and may provide insight into thyroid physiology and the pathophysiology of Pendred syndrome.
Assuntos
Proteínas de Transporte/genética , Proteínas de Transporte/metabolismo , Cloretos/metabolismo , Bócio/genética , Perda Auditiva Neurossensorial/genética , Iodetos/metabolismo , Proteínas de Membrana Transportadoras , Animais , Sequência de Bases , Células Cultivadas , Feminino , Humanos , Insetos/citologia , Insetos/metabolismo , Dados de Sequência Molecular , Oócitos/metabolismo , Ratos , Proteínas Recombinantes/genética , Proteínas Recombinantes/metabolismo , Transportadores de Sulfato , Síndrome , Xenopus laevisRESUMO
Congenital hypothyroidism (CH) due to thyroglobulin (TG) variants causes very low serum TG levels with normal or enlarged thyroid glands, depending on the severity of the defect, and with autosomal recessive inheritance. The purpose of this study was to functionally characterize p.Cys1281Tyr variant in the TG gene in order to increase our knowledge of the molecular mechanisms associated with CH. In order to find evidence that support the hypothesis that the p.Cys1281Tyr variant would affect the TG folding were performed amino acid prediction, 3D modeling and transient expression analysis in HEK293T cells. 18 of the 21â³in silico" algorithms predict a deleterious effect of the p.Cys1281Tyr variant. The full-length 3D model p.Cys1281Tyr TG showed disulfide bond cleavage between the cysteines at positions 1249 and 1281 and rearrangement of the TG structure, while transient expression analysis indicated that p.Cys1281Tyr causes retention of the protein inside the cell. Consequently, these results show that this pathogenic variant makes it impossible for TG to fulfill its function in the biosynthesis process of thyroid hormones, causing CH. In conclusion, our results confirm the pathophysiological importance of misfolding of TG as a consequence of p.Cys1281Tyr variant located in the hinge module/flap region of TG.