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1.
Am J Med Genet A ; 191(2): 400-407, 2023 02.
Artigo em Inglês | MEDLINE | ID: mdl-36345653

RESUMO

Interstitial microdeletions in the long arm of chromosome 3 are rare. In this study, we identified two patients with approximately 5-Mb overlapping deletions in the 3q26.2q26.31 region. Both patients showed neurodevelopmental delays, congenital heart defects, and distinctive facial features. One of them showed growth deficiency and brain abnormalities, as shown on a magnetic resonance imaging scan. Haploinsufficiency of NLGN1 and FNDC3B present in the common deletion region was considered to be responsible for neurodevelopmental delay and the distinctive features, respectively. The possibility of unmasked variants in PLD1 was considered and analyzed, but no possible pathogenic variant was found, and the mechanism of the congenital heart defects observed in the patients is unknown. Because 3q26.2q26.31 deletions are rare, more information is required to establish genotype-phenotype correlations associated with microdeletions in this region.


Assuntos
Cardiopatias Congênitas , Malformações do Sistema Nervoso , Humanos , Deleção Cromossômica , Fenótipo , Cardiopatias Congênitas/genética , Malformações do Sistema Nervoso/genética
3.
Pediatr Res ; 79(4): 543-8, 2016 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-26650342

RESUMO

BACKGROUND: Noonan syndrome (NS) is a clinically and genetically heterogeneous syndrome characterized by distinctive facial features, short stature, congenital heart diseases, and other comorbidities. NS-specific growth charts are essential for NS care, but currently no such charts are available for Asian populations. METHODS: We conducted a nationwide survey by collaborating with three academic societies in Japan. We obtained the data of 356 clinically diagnosed NS subjects from 20 hospitals. The Lambda-Mu-Sigma method was used for establishing growth charts. RESULTS: A total of 308 subjects (males: 159 and females: 149) were analyzed after excluding 48 subjects because of missing auxological data (26 subjects), presence of complications affecting growth (5 subjects), and extreme longitudinal growth aberrations which lay more than three standard deviation scores from the mean in this population (17 subjects). Genetic analyses were performed in 150 patients (48.7%); 103 (68.7%) were reported to have some abnormalities in the known causative genes. Cardiovascular diseases were found in 256 patients (83.1%). The NS-specific height, weight, and BMI charts were constructed with 3,249 mixed longitudinal and cross-sectional measurements. CONCLUSION: Growth standards for Japanese individuals with NS were established. These charts are expected to be used in various clinical settings.


Assuntos
Crescimento , Síndrome de Noonan/fisiopatologia , Feminino , Humanos , Japão , Masculino
4.
Clin Exp Nephrol ; 19(4): 678-82, 2015 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-25255780

RESUMO

BACKGROUND: Although congenital anomalies of the kidney and urinary tract (CAKUT) are the most common cause of pediatric end-stage renal disease (ESRD), little is known about the characteristics exhibited in the infantile period by CAKUT patients who develop ESRD. Further, an efficient screening method for CAKUT diagnosis is not available currently. In the present study, we aimed to develop a method to select infants who potentially have CAKUT from a large group of infants. METHODS: We retrospectively investigated the clinical characteristics of CAKUT patients in the infantile period. The medical records of 101 patients with CAKUT who had undergone dialysis or renal transplantation were reviewed. The data of gestational age, birth weight, oligohydramnios, poor body weight gain, asphyxia, and jaundice were recorded. We attempted to determine the ideal characteristics that could be used to select infants who potentially have CAKUT. RESULTS: 14 % of patients were born prematurely, 18 % had low birth weight, 79 % had poor body weight gain, 18 % had asphyxia, 8 % had oligohydramnios, and 12 % had jaundice. We found that 82 % of patients had poor body weight gain or oligohydramnios among our patients and regarded these two symptoms as ideal markers for selecting those who potentially have CAKUT (specificity, 95 %; efficacy, 95 %). Further, the age of ≤ 7 months was the most appropriate time for the selection. CONCLUSIONS: For timely diagnosis of CAKUT, we recommend that ultrasound examination and the serum creatinine test be conducted for infants showing poor body weight gain or oligohydramnios at age ≤ 7 months.


Assuntos
Anormalidades Urogenitais/diagnóstico , Adolescente , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Masculino , Seleção de Pacientes , Estudos Retrospectivos , Centros de Atenção Terciária/estatística & dados numéricos
5.
Pediatr Int ; 57(5): 880-3, 2015 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-26114601

RESUMO

BACKGROUND: To the best of our knowledge, this is the third report concerning 4q21q22 deletions. In this report, we describe the cases of two girls with 4q deletion and polycystic kidney disease. G-banding confirmed the deletion in one patient but not in the other. METHODS: We describe the cases of two girls with 4q deletion and polycystic kidney disease. Chromosomal deletions were mapped to 4q21-22. One patient had a simple 4q contiguous gene deletion, whereas the other patient had a complicated chromosomal rearrangement. In patient 1, a smaller part of the 4q deletion was translocated to the 3p region. RESULTS: Fifty-four genes and 72 genes were deleted in patients 1 and 2, respectively. In both patients, 52 genes were consistently deleted. CONCLUSION: The present two patients had a similar phenotype, including severe growth and developmental retardation, and a characteristic facial appearance. The loss of RPKG2 and RASGEF1B causes severe growth defect. PKD2 loss causes kidney cysts.


Assuntos
Anormalidades Múltiplas/genética , Transtornos Cromossômicos/genética , Deficiências do Desenvolvimento/genética , Deleção de Genes , Doenças Renais Policísticas/genética , Adulto , Pré-Escolar , Deleção Cromossômica , Transtornos Cromossômicos/diagnóstico , Cromossomos Humanos Par 4/genética , Feminino , Humanos , Recém-Nascido , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Linhagem , Fenótipo , Doenças Renais Policísticas/diagnóstico , Translocação Genética
7.
Am J Med Genet A ; 161A(9): 2167-73, 2013 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-23897656

RESUMO

Prader-Willi syndrome (PWS), a complex genetic disorder, arises from suppressed expression of paternally inherited imprinted genes on chromosome 15q11-q13. Characteristics include short stature, intellectual disability, behavioral problems, hypogonadism, obesity, and reduced bone and muscle mass. Testosterone replacement (TR) remains controversial due to concerns regarding behavioral problems. To evaluate the effects of TR on secondary sexual characteristics, body composition, and behavior in adult males with PWS, 22 male PWS patients over the age of 16 with behavioral scores of less than grade 4 on the Modified Overt Aggression Scale (MOAS) underwent monthly intramuscular TR (125 mg). Pubertal change, body composition and behavior were evaluated before and after 24 months of therapy. Serum testosterone, LH, and FSH did not change. Increased pubic hair was observed in 16 of 22 patients (72.7%). Percent body fat decreased from 47.55 ± 2.06% to 39.75 ± 1.60% (n = 18) (P = 0.018). Bone mineral density increased from 0.8505 ± 0.0426 g/cm(2) to 0.9035 ± 0.0465 g/cm(2) (n = 18) (P = 0.036), and lean body mass increased from 18093.4 ± 863.0 g to 20312.1 ± 1027.2 g (n = 18) (P = 0.009). The MOAS was unchanged, from 4.5 ± 2.0 at the beginning of the study to 3.0 ± 1.7 at the end of study indicating no increase in aggression. No behavioral problems were observed. Based on this pilot study, TR with 125 mg monthly is a potentially safe and useful intervention for adult males with PWS.


Assuntos
Comportamento/efeitos dos fármacos , Composição Corporal/efeitos dos fármacos , Terapia de Reposição Hormonal , Síndrome de Prader-Willi/tratamento farmacológico , Maturidade Sexual/efeitos dos fármacos , Testosterona/farmacologia , Testosterona/uso terapêutico , Adolescente , Adulto , Índice de Massa Corporal , Humanos , Masculino , Pessoa de Meia-Idade , Síndrome de Prader-Willi/sangue , Resultado do Tratamento , Adulto Jovem
8.
Am J Med Genet A ; 161A(9): 2339-46, 2013 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-23913798

RESUMO

Auriculocondylar syndrome (ACS) is a branchial arch syndrome typically inherited in an autosomal dominant fashion. Patients with ACS display the following core symptoms with varying severity: a specific malformation of the external ear, known as a "question mark ear," micrognathia and mandibular condyle hypoplasia. Recently, phospholipase C, ß 4 (PLCB4) mutations were identified as the major cause of autosomal dominant ACS, with mutations of the PLCB4 catalytic domain predicted to have a dominant negative effect. In addition, one ACS patient born to related parents harbored a homozygous partial deletion of PLCB4, and presented with ACS plus central apnea and macropenis; these features had not been previously reported in association with ACS. His parents, each with a heterozygous partial PLCB4 deletion, were phenotypically normal, suggesting autosomal recessive inheritance of ACS, with complete loss of function of PLCB4 predicted in the patient. We herein describe two brothers with ACS caused by compound heterozygous splice site mutations in PLCB4. The patients were born to the same unrelated and healthy parents, with each parent harboring one of the mutations, indicating autosomal recessive ACS. Both patients reported here had mixed apneas, gastrointestinal transit defects and macropenis, in addition to typical craniofacial features of ACS. This is the first example of ACS caused by compound heterozygous splice site mutations in PLCB4, the second autosomal recessive case of ACS confirmed by molecular analysis, and strengthens the link between complete loss of function of PLCB4 and extra-craniofacial features.


Assuntos
Otopatias/diagnóstico , Otopatias/genética , Orelha/anormalidades , Genes Recessivos , Mutação , Fenótipo , Fosfolipase C beta/genética , Adulto , Otopatias/sangue , Feminino , Humanos , Recém-Nascido , Cariótipo , Masculino , Linhagem , Sítios de Splice de RNA , Análise de Sequência de DNA
9.
Am J Med Genet A ; 161A(6): 1221-37, 2013 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-23637025

RESUMO

Mutations in the components of the SWItch/sucrose nonfermentable (SWI/SNF)-like chromatin remodeling complex have recently been reported to cause Coffin-Siris syndrome (CSS), Nicolaides-Baraitser syndrome (NCBRS), and ARID1B-related intellectual disability (ID) syndrome. We detail here the genotype-phenotype correlations for 85 previously published and one additional patient with mutations in the SWI/SNF complex: four with SMARCB1 mutations, seven with SMARCA4 mutations, 37 with SMARCA2 mutations, one with an SMARCE1 mutation, three with ARID1A mutations, and 33 with ARID1B mutations. The mutations were associated with syndromic ID and speech impairment (severe/profound in SMARCB1, SMARCE1, and ARID1A mutations; variable in SMARCA4, SMARCA2, and ARID1B mutations), which was frequently accompanied by agenesis or hypoplasia of the corpus callosum. SMARCB1 mutations caused "classical" CSS with typical facial "coarseness" and significant digital/nail hypoplasia. SMARCA4 mutations caused CSS without typical facial coarseness and with significant digital/nail hypoplasia. SMARCA2 mutations caused NCBRS, typically with short stature, sparse hair, a thin vermillion of the upper lip, an everted lower lip and prominent finger joints. A SMARCE1 mutation caused CSS without typical facial coarseness and with significant digital/nail hypoplasia. ARID1A mutations caused the most severe CSS with severe physical complications. ARID1B mutations caused CSS without typical facial coarseness and with mild digital/nail hypoplasia, or caused syndromic ID. Because of the common underlying mechanism and overlapping clinical features, we propose that these conditions be referred to collectively as "SWI/SNF-related ID syndromes".


Assuntos
Anormalidades Múltiplas/genética , Montagem e Desmontagem da Cromatina/genética , Face/anormalidades , Deformidades Congênitas do Pé/genética , Deformidades Congênitas da Mão/genética , Hipotricose/genética , Deficiência Intelectual/genética , Micrognatismo/genética , Pescoço/anormalidades , Fatores de Transcrição/genética , Proteínas Cromossômicas não Histona/genética , DNA Helicases/genética , Proteínas de Ligação a DNA/genética , Fácies , Feminino , Estudos de Associação Genética , Humanos , Masculino , Mutação , Proteínas Nucleares/genética , Proteína SMARCB1 , Síndrome
10.
Hum Genet ; 131(1): 121-30, 2012 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-21735174

RESUMO

X-chromosome inactivation (XCI) is an essential mechanism in females that compensates for the genome imbalance between females and males. It is known that XCI can spread into an autosome of patients with X;autosome translocations. The subject was a 5-year-old boy with Prader-Willi syndrome (PWS)-like features including hypotonia, hypo-genitalism, hypo-pigmentation, and developmental delay. G-banding, fluorescent in situ hybridization, BrdU-incorporated replication, human androgen receptor gene locus assay, SNP microarrays, ChIP-on-chip assay, bisulfite sequencing, and real-time RT-PCR were performed. Cytogenetic analyses revealed that the karyotype was 46,XY,der(X)t(X;15)(p21.1;q11.2),-15. In the derivative chromosome, the X and half of the chromosome 15 segments showed late replication. The X segment was maternal, and the chromosome 15 region was paternal, indicating its post-zygotic origin. The two chromosome 15s had a biparental origin. The DNA methylation level was relatively high in the region proximal from the breakpoint, and the level decreased toward the middle of the chromosome 15 region; however, scattered areas of hypermethylation were found in the distal region. The promoter regions of the imprinted SNRPN and the non-imprinted OCA2 genes were completely and half methylated, respectively. However, no methylation was found in the adjacent imprinted gene UBE3A, which contained a lower density of LINE1 repeats. Our findings suggest that XCI spread into the paternal chromosome 15 led to the aberrant hypermethylation of SNRPN and OCA2 and their decreased expression, which contributes to the PWS-like features and hypo-pigmentation of the patient. To our knowledge, this is the first chromosome-wide methylation study in which the DNA methylation level is demonstrated in an autosome subject to XCI.


Assuntos
Cromossomos Humanos Par 15/genética , Cromossomos Humanos X/genética , Impressão Genômica , Síndrome de Prader-Willi/genética , Translocação Genética/genética , Inativação do Cromossomo X , Biomarcadores/metabolismo , Pré-Escolar , Aberrações Cromossômicas , Bandeamento Cromossômico , Metilação de DNA , Perfilação da Expressão Gênica , Humanos , Hibridização in Situ Fluorescente , Cariótipo , Masculino , Proteínas de Membrana Transportadoras/genética , Análise de Sequência com Séries de Oligonucleotídeos , Fenótipo , Polimorfismo de Nucleotídeo Único/genética , RNA Mensageiro/genética , Reação em Cadeia da Polimerase em Tempo Real , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Proteínas Centrais de snRNP/genética
11.
Am J Med Genet A ; 158A(6): 1477-80, 2012 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-22585665

RESUMO

There have been multiple reports regarding the growth hormone (GH) secretion in patients with Prader-Willi syndrome (PWS). However, none have compared GH secretion in children with deletion group to those with maternal uniparental disomy (UPD). We evaluated the GH secretion in pediatric patients with PWS. Seventy-six patients with a deletion (n = 55) or UPD (n = 21) were studied. The secretion of GH by insulin stimulation in the patients with UPD (3.6 ± 2.2 ng/ml) was significantly lower than those with deletions (peak GH level: 11.1 ± 8.6 ng/ml; P = 0.0013). We also compared the response to GH replacement therapy. Yearly improvements in height standard deviation score (SDS) were similar in the two groups (first year SDS: 0.47 ± 0.47, deletion; 0.68 ± 0.26, UPD; P = 0.14).


Assuntos
Estatura , Genótipo , Hormônio do Crescimento/metabolismo , Síndrome de Prader-Willi/genética , Síndrome de Prader-Willi/metabolismo , Adolescente , Criança , Pré-Escolar , Deleção Cromossômica , Feminino , Hormônio do Crescimento/uso terapêutico , Terapia de Reposição Hormonal , Humanos , Lactente , Masculino , Síndrome de Prader-Willi/tratamento farmacológico , Resultado do Tratamento , Dissomia Uniparental
12.
J Med Genet ; 48(1): 32-7, 2011 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-21037275

RESUMO

BACKGROUND: Desbuquois dysplasia (DD) is a recessively inherited condition characterised by short stature, generalised skeletal dysplasia and advanced bone maturation. DD is both clinically and radiographically heterogeneous, and two subtypes have been distinguished based on the presence (type 1) or absence (type 2) of an accessory metacarpal bone. In addition, an apparently distinct variant without additional metacarpal bone but with short metacarpals and long phalanges (Kim variant) has been described recently. Mutations in the gene that encodes for CANT1 (calcium-activated nucleotidase 1) have been identified in a subset of patients with DD type 1. METHODS: A series of 11 subjects with DD from eight families (one type 1, two type 2, five Kim variant) were examined for CANT1 mutations by direct sequencing of all coding exons and their flanking introns. RESULTS: Eight distinct mutations were identified in seven families (one type 1, one type 2 and all 5 Kim variant): three were nonsense and five were missense. All missense mutations occurred at highly conserved amino acids in the nucleotidase conserved regions of CANT1. Measurement of nucleotidase activity in vitro showed that the missense mutations were all associated with loss-of-function. CONCLUSION: The clinical-radiographic spectrum produced by CANT1 mutations must be extended to include DD type 2 and Kim variant. While presence or absence of an additional metacarpal ossification centre has been used to distinguish subtypes of DD, this sign is not a distinctive criterion to predict the molecular basis in DD.


Assuntos
Mutação de Sentido Incorreto/genética , Nucleotidases/genética , Sequência de Aminoácidos , Animais , Células COS , Pré-Escolar , Chlorocebus aethiops , Anormalidades Craniofaciais/classificação , Anormalidades Craniofaciais/complicações , Anormalidades Craniofaciais/diagnóstico por imagem , Anormalidades Craniofaciais/genética , Nanismo/classificação , Nanismo/complicações , Nanismo/diagnóstico por imagem , Nanismo/genética , Mãos/diagnóstico por imagem , Deformidades Congênitas da Mão/complicações , Deformidades Congênitas da Mão/diagnóstico por imagem , Humanos , Instabilidade Articular/classificação , Instabilidade Articular/complicações , Instabilidade Articular/diagnóstico por imagem , Instabilidade Articular/genética , Dados de Sequência Molecular , Nucleotidases/química , Ossificação Heterotópica/classificação , Ossificação Heterotópica/complicações , Ossificação Heterotópica/diagnóstico por imagem , Ossificação Heterotópica/genética , Polidactilia/classificação , Polidactilia/complicações , Polidactilia/diagnóstico por imagem , Polidactilia/genética , Radiografia , Alinhamento de Sequência
14.
J Hum Genet ; 56(5): 398-400, 2011 May.
Artigo em Inglês | MEDLINE | ID: mdl-21412251

RESUMO

Desbuquois dysplasia (DBQD) is a severe skeletal dysplasia of autosomal recessive inheritance. DBQD is classified into types 1 and 2 based on presence or absence of hand anomalies. In a previous study, we found a CANT1 (for calcium-activated nucleotidase 1) mutation, c.676G>A in five DBQD families. They were all East Asians (Japanese or Korean). The high prevalence of the same mutation among Japanese and Korean suggested that it is a common founder mutation in the two populations. To examine a possible common founder, we examined the region around CANT1 in chromosomes with c.676G>A mutation by genotyping polymorphic markers in the region for the families. We examined their haplotypes using the family data. We identified in all families a common haplotype containing the CANT1 mutation that ranged up to 550 kb. The two unrelated carriers of the mutation in general populations in Korea and Japan could also have the haplotype. We estimated the age of the founder mutation as ∼ 1420 years (95% CI=880-1940 years). The c.676G>A mutation of CANT1 commonly seen in Japanese and Korean DBQD should be derived from a common founder.


Assuntos
Doenças do Desenvolvimento Ósseo/genética , Efeito Fundador , Mutação/genética , Nucleotidases/genética , Haplótipos , Humanos , Japão , Coreia (Geográfico) , Polimorfismo de Nucleotídeo Único/genética
15.
Hum Mutat ; 31(3): 284-94, 2010 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-20052757

RESUMO

Noonan syndrome (NS) and related disorders are autosomal dominant disorders characterized by heart defects, facial dysmorphism, ectodermal abnormalities, and mental retardation. The dysregulation of the RAS/MAPK pathway appears to be a common molecular pathogenesis of these disorders: mutations in PTPN11, KRAS, and SOS1 have been identified in patients with NS, those in KRAS, BRAF, MAP2K1, and MAP2K2 in patients with CFC syndrome, and those in HRAS mutations in Costello syndrome patients. Recently, mutations in RAF1 have been also identified in patients with NS and two patients with LEOPARD (multiple lentigines, electrocardiographic conduction abnormalities, ocular hypertelorism, pulmonary stenosis, abnormal genitalia, retardation of growth, and sensorineural deafness) syndrome. In the current study, we identified eight RAF1 mutations in 18 of 119 patients with NS and related conditions without mutations in known genes. We summarized clinical manifestations in patients with RAF1 mutations as well as those in NS patients withPTPN11, SOS1, or KRAS mutations previously reported. Hypertrophic cardiomyopathy and short stature were found to be more frequently observed in patients with RAF1 mutations. Mutations in RAF1 were clustered in the conserved region 2 (CR2) domain, which carries an inhibitory phosphorylation site (serine at position 259; S259). Functional studies revealed that the RAF1 mutants located in the CR2 domain resulted in the decreased phosphorylation of S259, and that mutant RAF1 then dissociated from 14-3-3, leading to a partial ERK activation. Our results suggest that the dephosphorylation of S259 is the primary pathogenic mechanism in the activation of RAF1 mutants located in the CR2 domain as well as of downstream ERK.


Assuntos
Mutação , Síndrome de Noonan/genética , Proteínas Proto-Oncogênicas c-raf/genética , Serina/genética , Proteínas 14-3-3/metabolismo , Animais , Cardiomiopatias/genética , Fácies , Humanos , Camundongos , Modelos Genéticos , Células NIH 3T3 , Fosforilação , Ligação Proteica , Proteína Tirosina Fosfatase não Receptora Tipo 11/genética
16.
Am J Med Genet A ; 152A(4): 875-85, 2010 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-20358597

RESUMO

We present the clinical and radiological findings of seven patients with a seemingly new variant of Desbuquois dysplasia (DBQD) and emphasize the radiographic findings in the hand. All cases showed remarkably accelerated carpal bone ages in childhood, but none of the patients had an accessory ossification center distal to the second metacarpal, or thumb anomalies, instead, there was shortness of one or all metacarpals, with elongated appearance of phalanges, resulting in nearly equal length of the second to fifth fingers. The two sibs followed for 20 years showed narrowing and fusion of the intercarpal joints with age and ultimately, precocious degenerative arthritis. The changes in the feet were similar to those of the hands, with advanced tarsal bone ages, shortness of the metatarsals and elongation of the second and third toes. Other radiographic findings were narrowness of the intervertebral disc spaces resulting in precocious degenerative spondylosis and progressive scoliosis. The femoral neck was short and thick and showed a persistent enlargement of the lesser trochanter with a high-riding, bulbous greater trochanter that became more prominent with age. Molecular testing of the diastrophic dysplasia sulfate transporter (DTDST) gene was performed on six patients and no mutations were detected. This radiographic and clinical observation further adds to the evidence that there may be subtypes of DBQD. Long-term follow-up showed that severe precocious osteoarthritis of the hand and spine is a major manifestation of this specific variant.


Assuntos
Determinação da Idade pelo Esqueleto , Doenças do Desenvolvimento Ósseo/diagnóstico por imagem , Ossos do Carpo/diagnóstico por imagem , Falanges dos Dedos da Mão/anormalidades , Falanges dos Dedos da Mão/diagnóstico por imagem , Ossos Metacarpais/anormalidades , Ossos Metacarpais/diagnóstico por imagem , Adolescente , Adulto , Doenças do Desenvolvimento Ósseo/complicações , Ossos do Carpo/anormalidades , Criança , Pré-Escolar , Feminino , Deformidades Congênitas do Pé/complicações , Deformidades Congênitas do Pé/diagnóstico por imagem , Deformidades Congênitas da Mão/complicações , Deformidades Congênitas da Mão/diagnóstico por imagem , Humanos , Joelho/anormalidades , Joelho/diagnóstico por imagem , Masculino , Pelve/anormalidades , Pelve/diagnóstico por imagem , Irmãos , Coluna Vertebral/anormalidades , Coluna Vertebral/diagnóstico por imagem , Adulto Jovem
17.
Am J Med Genet A ; 149A(4): 598-601, 2009 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-19253382

RESUMO

We report on a girl with early onset Huntington disease (HD). Her initial symptoms at 2 years of age included oral motor dysfunction and gait disturbance. Magnetic resonance imaging of the head revealed severe atrophy of both the vermis and the cerebellar cortex in addition to the common findings of basal ganglia including the caudate nuclei, putamen, and globus pallidus. Molecular analysis showed 160 CAG repeats in the HD gene. This mutation was inherited from her mother who was also affected, with a HD CAG expansion of 60 repeats. Cerebellar symptoms should be considered as a manifestation of early onset HD.


Assuntos
Cerebelo/patologia , Doença de Huntington/genética , Doença de Huntington/patologia , Idade de Início , Antecipação Genética , Atrofia , Sequência de Bases , Pré-Escolar , Primers do DNA/genética , Feminino , Humanos , Proteína Huntingtina , Imageamento por Ressonância Magnética , Mães , Proteínas do Tecido Nervoso/genética , Proteínas Nucleares/genética , Expansão das Repetições de Trinucleotídeos
19.
Clin Dysmorphol ; 17(1): 31-34, 2008 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-18049078

RESUMO

No causative gene has been found for idiopathic central precocious puberty; and FOXP2, located in 7q31, is the only known gene for speech and language disturbances. We report a girl with central precocious puberty, moderate mental retardation, and severe speech impairment; accompanied by a de-novo balanced translocation between 7q31 and 10p14. Physical mapping through molecular cytogenetic investigations demonstrated the breakpoints of 7q31 and 10p14 within a bacterial artificial chromosome (BAC) clone RP11-124G5 and a cosmid clone derived from a BAC clone RP11-1122C18, respectively. FOXP2 was found to be localized approximately 500 kb distant from the centromeric end of the disrupted BAC RP11-124G5 at the 7q31 breakpoint. Speech impairment in the girl might be derived from dysfunction of FOXP2 by a position effect of the 7q31 translocation breakpoint.


Assuntos
Cromossomos Humanos Par 10 , Cromossomos Humanos Par 7 , Deficiência Intelectual/genética , Distúrbios da Fala/genética , Translocação Genética , Pré-Escolar , Cromossomos Artificiais Bacterianos , Feminino , Fatores de Transcrição Forkhead/genética , Humanos
20.
BMC Mol Biol ; 8: 84, 2007 Sep 21.
Artigo em Inglês | MEDLINE | ID: mdl-17888164

RESUMO

BACKGROUND: The homeodomain-containing transcription factor PITX3 was shown to be essential for normal eye development in vertebrates. Human patients with point mutations in PITX3 demonstrate congenital cataracts along with anterior segment defects in some cases when one allele is affected and microphthalmia with brain malformations when both copies are mutated. The functional consequences of these human mutations remain unknown. RESULTS: We studied the PITX3 mutant proteins S13N and G219fs to determine the type and severity of functional defects. Our results demonstrate alterations in DNA-binding profiles and/or transactivation activities and suggest a partial loss-of-function in both mutants with the G219fs form being more severely affected. No anomalies in cellular distribution and no dominant-negative effects were discovered for these mutants. Interestingly, the impairment of the G219fs activity varied between different ocular cell lines. CONCLUSION: The G219fs mutation was found in multiple families affected with congenital cataracts along with anterior segment malformations in many members. Our data suggest that the presence/severity of anterior segment defects in families affected with G219fs may be determined by secondary factors that are expressed in the developing anterior segment structures and may modify the effect(s) of this mutation. The S13N mutant showed only minor alteration of transactivation ability and DNA binding pattern and may represent a rare polymorphism in the PITX3 gene. A possible contribution of this mutation to human disease needs to be further investigated.


Assuntos
Anormalidades Múltiplas/genética , Proteínas de Homeodomínio/genética , Mutação/genética , Fatores de Transcrição/genética , Anormalidades Múltiplas/patologia , Animais , Segmento Anterior do Olho/patologia , Sequência de Bases , Catarata/genética , Análise Mutacional de DNA/métodos , Cães , Regulação da Expressão Gênica no Desenvolvimento/genética , Genes Homeobox/genética , Marcadores Genéticos , Predisposição Genética para Doença , Humanos , Cristalino/patologia , Camundongos , Microftalmia/genética , Microftalmia/patologia , Dados de Sequência Molecular , Malformações do Sistema Nervoso/genética , Malformações do Sistema Nervoso/patologia , Fenótipo , Ratos , Alinhamento de Sequência , Homologia de Sequência , Ativação Transcricional/genética
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