RESUMO
BACKGROUND: Autism spectrum disorder (ASD) has a complex genetic etiology. Some symptoms and mutated genes, including neuroligin (NLGN), neurexin (NRXN), and SH3 and multiple ankyrin repeat domains protein (SHANK), are shared by schizophrenia and ASD. Little is known about the molecular pathogenesis of ASD. One of the possible molecular pathogenesis is an imbalance of excitatory and inhibitory receptors linked with the NLGN-PSD-95-SHANK complex via postsynaptic density protein/Drosophila disc large tumor suppressor/zonula occludens-1 protein (PDZ) binding. In the present study, we focused on GPR85 as a candidate gene for ASD because the C-terminal amino acid sequence of GPR85 [Thr-Cys-Val-Ile (YCVI)] is classified as a type II PDZ-binding motif, and GPR85 is a risk factor for schizophrenia. GPR85 is an orphan receptor that regulates neural and synaptic plasticity and modulates diverse behaviors, including learning and memory. While searching for molecules that associate with GPR85, we found that GPR85 was associated with postsynaptic density protein (PSD)-95 linked with NLGN in the brain. METHODS: We examined the proteins that associate with the C-terminal sequence of GPR85 by pull-down assay and immunoblot analysis and searched for a mutation of the GPR85 gene in patients with ASD. We used immunostaining to examine the intracellular localization of mutated GPR85 and its influence on the morphology of cells and neurons. RESULTS: The C-terminal sequence of GPR85 interacted with PSD-95 at PDZ1, while NLGN interacted with PSD-95 at PDZ3. Two male patients with ASD from independent Japanese families possessed inherited missense mutations at conserved sites in GPR85: one had T1033C (M152T) and the other had G1239T (V221L). These mutations were located in a domain related to G protein interaction and signal transduction. In contrast to wild-type GPR85, mutated GPR85 was more preferentially accumulated, causing endoplasmic reticulum stress, and disturbed the dendrite formation of hippocampal neurons. CONCLUSIONS: GPR85 associated with the PSD-95 linked with NLGN, which is related to ASD. GPR85 carrying the mutations detected in ASD patients disturbed dendrite formation that could be the candidate for molecular pathogenesis of ASD through the associated NLGN-PSD-95 receptor complex.
RESUMO
A patient with acute lymphoblastic leukemia who was hypersensitive to native Escherichia coli L-asparaginase (L-asp) underwent readministration of the L-asp without serious adverse effects for 11 doses using a desensitization protocol every time. Monitoring of anti-L-asp antibody and L-asp activity levels revealed that the serum L-asp activity was below the effective levels during the administration of first 6 to 7 doses because of extremely high levels of anti-L-asp IgG. Sustained L-asp activity was attained since the eighth dose was administered, when the antibody levels were <5 U/mL. L-asp activity levels in patients with L-asp hypersensitivity should be monitored during the desensitization courses to ensure a sufficient L-asp activity.
Assuntos
Antineoplásicos/imunologia , Asparaginase/imunologia , Dessensibilização Imunológica/métodos , Hipersensibilidade a Drogas/imunologia , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Asparagina/metabolismo , Pré-Escolar , Hipersensibilidade a Drogas/sangue , Ensaio de Imunoadsorção Enzimática , Escherichia coli/imunologia , Humanos , MasculinoRESUMO
Williams-Beuren syndrome (WBS) is a multisystemic genetic disorder caused by a contiguous gene deletion at 7q11.23. We report a severely affected WBS patient with cerebral and cerebellar dysplasia as well as hypertrophic cardiomyopathy. Microarray comparative genomic hybridization (aCGH) detected a deletion on 7q11.23 expanding from RP11-614D7 to RP11-137E8, which is a typical deletion in WBS. To the best of our knowledge, this is the first case report of a WBS patient with severe congenital central nervous system anomaly and progressive hypertrophic cardiomyopathy. The relationship between the genes deleted in WBS and a CNS anomaly plus hypertrophic cardiomyopathy requires further analysis.
Assuntos
Encéfalo/anormalidades , Cardiomiopatia Hipertrófica/fisiopatologia , Deleção Cromossômica , Cromossomos Humanos Par 7 , Síndrome de Williams/genética , Encéfalo/patologia , Cardiomiopatia Hipertrófica/genética , Hibridização Genômica Comparativa , Ecocardiografia , Evolução Fatal , Humanos , Lactente , Imageamento por Ressonância Magnética , Masculino , Análise em Microsséries , Tomografia Computadorizada por Raios X , Síndrome de Williams/patologia , Síndrome de Williams/fisiopatologiaRESUMO
Tubulointerstitial nephritis and uveitis (TINU) syndrome, which was first described in 1975, has been reported in more than 130 patients, mostly in adolescent or young women. Although data concerning the etiologic background of this inflammatory disease are limited, several humoral factors, including cytokines, have been reported in association with the disease. Here, we report a case of TINU in a 14-year-old girl, whose renal and ophthalmological improvement was associated with the decrease of serum levels of tumor necrosis factor-α (TNF-α), interferon-γ (IFN-γ), and interleukin-8 (IL-8). This suggests the presence of T-cell-mediated immunity in this unique syndrome.
RESUMO
The ribosomal protein S6 kinase, 90 kb, polypeptide 3 gene (RPS6KA3) is responsible for Coffin-Lowry syndrome (CLS), which is characterized by intellectual disability (ID) and facial and bony abnormalities. This gene also affects nonsyndromic X-linked ID and nonsyndromic X-linked ID without bony abnormalities. Two families have been previously reported to have genetic microduplication including RPS6KA3. In the present study, we used array-comparative genomic hybridization (CGH) analysis with Agilent Human genome CGH 180K and detected a 584-kb microduplication spanning 19.92-20.50 Mb of Xp22.12 (including RPS6KA3) in the members of one family, including three brothers, two sisters, and their mother. The 15-year-old male proband and one of his brothers had mild ID and localization-related epilepsy, whereas his other brother presented borderline intelligence quotient (IQ) and attention-deficit-hyperactivity disorder (ADHD). One sister presented pervasive development disorder (PDD). Analysis of this family suggests that RPS6KA3 duplication is responsible for mild ID, ADHD, and localization-related epilepsy, and possibly for PDD.
Assuntos
Transtorno do Deficit de Atenção com Hiperatividade/genética , Transtornos Globais do Desenvolvimento Infantil/genética , Cromossomos Humanos X/genética , Epilepsias Parciais/genética , Proteínas Quinases S6 Ribossômicas 90-kDa/genética , Adolescente , Adulto , Transtorno do Deficit de Atenção com Hiperatividade/complicações , Criança , Transtornos Globais do Desenvolvimento Infantil/complicações , Pré-Escolar , Epilepsias Parciais/complicações , Feminino , Duplicação Gênica , Humanos , Masculino , LinhagemRESUMO
Mutations in the synaptic adhesion protein CADM1 (RA175/SynCAM1) are associated with autism spectrum disorder (ASD), a neurodevelopmental disorder of uncertain molecular origin. Cadm1-knock out (KO) mice exhibit smaller cerebella with decreased number of synapse of Purkinje cells and some ASD-like symptoms, including impaired ultrasonic vocalization. In this study, we examined the alteration of the Cadm1 synaptic complex in the mouse cerebellum at post-natal stages. The C-terminal peptide of Cadm1 associated with Mupp1 at PSD-95/Dlg/ZO-1 (PDZ)(1-5), a scaffold protein containing 13 PDZ domains, which interacted with gamma-aminobutyric acid type B receptor (GABBR)2 at PDZ13, but not with PSD-95. The GABBR2 was detected in a set of proteins interacting with Cadm1 C-terminal. Cadm1 colocalized with Mupp1 and GABBR2 on the dendrites of Purkinje cells in the molecular layers of the developing cerebellum and on the dendrites of hippocampal neurons cultured in vitro. These observations suggest that the Cadm1 synaptic receptor complex, including Mupp1-GABBR2, is located on the dendrites of Purkinje cells. The amount of GABBR2 protein, but not mRNA, was increased in the cerebella of Cadm1 KO mice, suggesting that lack of Cadm1 does not affect transcription of GABBR2, but may stabilize the Mupp1-GABBR2 complex; the Mupp1-GABBR2 interaction may be stabilized by conformational change in Mupp1 or association with other adhesion molecules and by anchorage to the post-synaptic membrane. Up-regulation of GABBR2 in the cerebellum in the absence of CADM1 may be associated with ASD pathogenesis.
Assuntos
Proteínas de Transporte/metabolismo , Moléculas de Adesão Celular/metabolismo , Cerebelo/metabolismo , Transtornos Globais do Desenvolvimento Infantil/metabolismo , Imunoglobulinas/metabolismo , Receptores de GABA-B/metabolismo , Animais , Molécula 1 de Adesão Celular , Criança , Dendritos/metabolismo , Modelos Animais de Doenças , Humanos , Immunoblotting , Imuno-Histoquímica , Imunoprecipitação , Proteínas de Membrana , Camundongos , Camundongos Knockout , Células de Purkinje/metabolismo , Reação em Cadeia da Polimerase em Tempo RealRESUMO
A 13-yr-old boy with recurrent acute myeloid leukemia underwent HSCT using cells from an unrelated donor who matched all HLA antigens except one. Forty-two days later, the patient developed a steroid-refractory hepatitic variant of liver GVHD with peak ALT and T.Bil values of 1406 mU/mL and 10.4 mg/dL, respectively. He was successfully treated with pulse Cy (1000 mg/dose × one day) without a change in chimerism being observed or acquiring an infection. All immunosuppressant therapies could be discontinued 12 months after HSCT. Two yr after HSCT, the patient remains in CR without chronic GVHD. This single case report suggests that pulse Cy may be a promising therapy for steroid-refractory GVHD, especially hepatitic GVHD, but needs to be further tested in clinical trials.
Assuntos
Ciclofosfamida/administração & dosagem , Doença Enxerto-Hospedeiro/terapia , Hepatite/tratamento farmacológico , Falência Hepática/terapia , Falência Hepática/virologia , Esteroides/efeitos adversos , Adolescente , Resistência a Medicamentos , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Humanos , Imunossupressores/uso terapêutico , Leucemia Mieloide Aguda/complicações , Leucemia Mieloide Aguda/terapia , Masculino , Fatores de Tempo , Condicionamento Pré-Transplante/efeitos adversos , Transplante Homólogo , Resultado do TratamentoRESUMO
Foxp2(R552H) knock-in (KI) mouse pups with a mutation related to human speech-language disorders exhibit poor development of cerebellar Purkinje cells and impaired ultrasonic vocalization (USV), a communication tool for mother-offspring interactions. Thus, human speech and mouse USV appear to have a Foxp2-mediated common molecular basis in the cerebellum. Mutations in the gene encoding the synaptic adhesion molecule CADM1 (RA175/Necl2/SynCAM1/Cadm1) have been identified in people with autism spectrum disorder (ASD) who have impaired speech and language. In the present study, we show that both Cadm1-deficient knockout (KO) pups and Foxp2(R552H) KI pups exhibit impaired USV and smaller cerebellums. Cadm1 was preferentially localized to the apical-distal portion of the dendritic arbor of Purkinje cells in the molecular layer of wild-type pups, and VGluT1 level decreased in the cerebellum of Cadm1 KO mice. In addition, we detected reduced immunoreactivity of Cadm1 and VGluT1 on the poorly developed dendritic arbor of Purkinje cells in the Foxp2(R552H) KI pups. However, Cadm1 mRNA expression was not altered in the Foxp2(R552H) KI pups. These results suggest that although the Foxp2 transcription factor does not target Cadm1, Cadm1 at the synapses of Purkinje cells and parallel fibers is necessary for USV function. The loss of Cadm1-expressing synapses on the dendrites of Purkinje cells may be associated with the USV impairment that Cadm1 KO and Foxp2(R552H) KI mice exhibit.
Assuntos
Moléculas de Adesão Celular/metabolismo , Dendritos/metabolismo , Imunoglobulinas/metabolismo , Células de Purkinje/metabolismo , Sinapses/metabolismo , Vocalização Animal , Animais , Molécula 1 de Adesão Celular , Moléculas de Adesão Celular/genética , Cerebelo/anormalidades , Cerebelo/metabolismo , Criança , Transtornos Globais do Desenvolvimento Infantil/genética , Dendritos/genética , Feminino , Fatores de Transcrição Forkhead/genética , Fatores de Transcrição Forkhead/metabolismo , Genótipo , Humanos , Immunoblotting , Imunoglobulinas/genética , Imuno-Histoquímica , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Transgênicos , Mutação , Proteínas Repressoras/genética , Proteínas Repressoras/metabolismo , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Distúrbios da Fala/genética , Ultrassom , Proteína Vesicular 1 de Transporte de Glutamato/metabolismoRESUMO
A one-year-old boy with neuroblastoma (NBoma)-associated opsoclonus-myoclonus syndrome (OMS) was treated by oral high-dose dexamethasone (DEX) pulses (20 mg/m(2)/day of DEX for three consecutive days) every 28 days for 6 months after resection of the tumor. All OMS symptoms improved after the first course of DEX pulse therapy and disappeared after the last course. No adverse effects were observed. Minor deterioration of his developmental quotient was noted 33 months after the onset of the disease. NBoma remission has been maintained since treatment. Before DEX pulse therapy, frequency of T lymphocyte, in particular CD4-positive cell decreased markedly resulted in low CD4/8 ratio in the peripheral blood (PB). The frequency of B lymphocyte increased, especially in cerebrospinal fluid. These aberrant values in PB were reversed by DEX pulse therapy and correlated well with the neurological symptoms. A prospective study that assesses the efficacy of this promising and inexpensive treatment for OMS is warranted.
Assuntos
Anti-Inflamatórios/administração & dosagem , Biomarcadores/sangue , Dexametasona/administração & dosagem , Síndrome de Opsoclonia-Mioclonia/tratamento farmacológico , Linfócitos B/imunologia , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD8-Positivos/imunologia , Pré-Escolar , Humanos , Neoplasias Renais/complicações , Neoplasias Renais/imunologia , Masculino , Neuroblastoma/complicações , Neuroblastoma/imunologia , Síndrome de Opsoclonia-Mioclonia/etiologia , Síndrome de Opsoclonia-Mioclonia/imunologiaRESUMO
We present here a 25-year-old woman with genetically confirmed (p.R276L mutation in the GFAP gene) juvenile-onset AxD. Episodic vomiting appeared at age nine, causing anorexia and insufficient growth. Brain MRI at age 11 showed a small nodular lesion with contrast enhancement in the left dorsal portion of the cervicomedullary junction. Her episodic vomiting improved spontaneously at age 13, and she became neurologically asymptomatic. The enhancement of the lesion disappeared simultaneously, although the plaque remained. Longitudinal MRI observations, however, revealed insidiously progressive cervicomedullary atrophy without a signal change. This case broadens our knowledge of AxD: (1) molecular analysis of the GFAP gene is warranted in patients with MRI evidence of tumor-like lesions in the brainstem, particularly if they present with isolated episodic vomiting and/or anorexia; (2) the disease can be self-remitting for at least 12 years; (3) cervicomedullary atrophy, characteristic of the adult form, can be insidiously progressive without a signal change before the clinical symptoms appear.
Assuntos
Doença de Alexander/patologia , Vértebras Cervicais/patologia , Progressão da Doença , Bulbo/patologia , Adulto , Doença de Alexander/genética , Atrofia/patologia , Feminino , Humanos , Doenças do Sistema Nervoso/genética , Doenças do Sistema Nervoso/patologia , Fatores de TempoRESUMO
A hepatitis C virus (HCV) strain (HC10-0804) recovered from a 12-year-old Japanese female with chronic hepatitis C segregated into discordant genotypes, 2b and 1b, in the 5'UTR/core and NS5B regions, respectively, thus suggesting an inter-genotypic recombination. The HC10-0804 isolate had a genomic length of 9,423 nucleotides (nt), excluding the poly(U) tract at the 3' terminus, and encoded a single open reading frame (ORF) for a polyprotein of 3,014 amino acids (aa). Based on Simplot and Bootscan analyses, the crossover point from 2b to 1b was estimated at nt 3443/3444 (aa 1034/1035), just after the beginning of the NS3 region. Comparison of the entire genomic sequence showed that the HC10-0804 strain was only 90.2% identical to the previously reported 2b/1b recombinant strain (SE-03-07-1689) from the Philippines, whose putative crossover point was 24 nt downstream of that of HC10-0804. These results indicate the circulation of a novel inter-genotypic (2b/1b) recombinant HCV in Japan.
Assuntos
Genótipo , Hepacivirus/genética , Hepatite C/virologia , Vírus Reordenados/genética , Criança , Feminino , Hepacivirus/classificação , Hepatite C/epidemiologia , Humanos , Japão/epidemiologia , Dados de Sequência Molecular , Fatores de TempoAssuntos
Linfócitos T CD8-Positivos/imunologia , Linfoma Cutâneo de Células T/patologia , Neoplasias Cutâneas/patologia , Biópsia , Linfócitos T CD8-Positivos/patologia , Criança , Diagnóstico Diferencial , Evolução Fatal , Feminino , Seguimentos , Humanos , Linfoma Cutâneo de Células T/imunologia , Índice de Gravidade de Doença , Neoplasias Cutâneas/imunologiaRESUMO
A preterm infant with very low birth weight was born with fetal onset familial hemophagocytic lymphohistiocytosis. Known gene abnormalities responsible for the disease were not identified in the patient. The infant died at 13 months of age owing to complications from cord blood stem cell transplantation. We found selectively elevated expression of interleukin-6 and chemokines in the cord blood of the patient. We also reviewed 7 other preterm cases of congenital hemophagocytic lymphohistiocytosis to highlight the significance of this condition, as it can cause ascites and hepatosplenomegaly in utero and be mistaken for congenital infection in the fetus.
Assuntos
Citocinas/imunologia , Recém-Nascido Prematuro , Linfo-Histiocitose Hemofagocítica/congênito , Linfo-Histiocitose Hemofagocítica/imunologia , Humanos , Recém-Nascido , MasculinoRESUMO
A 5-year-old girl presented with abdominal pain and bloody stools 2 weeks after suffering from influenza A infection. Enhanced computed tomographic scan showed widespread splanchnic venous thrombosis and small intestine necrosis. She recovered after the necrotic bowel was resected. The patient continues to receive anticoagulant therapy. Thrombophilia screening after the complete resolution consistently showed mildly decreased protein S (PS) activity with normal PS antigen levels. Sequence analysis detected a heterozygous K196E mutation in the PROS1 gene. Type 2 PS deficiency was diagnosed. This is the first report of mesenteric vein thrombosis in a child with a type 2 PS deficiency.
Assuntos
Oclusão Vascular Mesentérica/genética , Deficiência de Proteína S/complicações , Trombose Venosa/genética , Antivirais/uso terapêutico , Proteínas Sanguíneas/genética , Pré-Escolar , Feminino , Humanos , Vírus da Influenza A , Influenza Humana/complicações , Influenza Humana/tratamento farmacológico , Intestinos/irrigação sanguínea , Intestinos/cirurgia , Isquemia/genética , Isquemia/cirurgia , Oclusão Vascular Mesentérica/cirurgia , Mutação , Oseltamivir/uso terapêutico , Proteína S , Deficiência de Proteína S/genética , Trombose Venosa/cirurgiaRESUMO
Cow's milk allergy (CMA) in the neonatal period is thought to include several clinical conditions, yet the pathophysiology remains unclear. We report here the case of a term newborn infant who showed hematochezia 36 hours after the first feeding with cow's milk formula. His serum immunoglobulin E levels were not elevated, although eosinophils were detected in the stool. Elimination of cow's milk formula resolved the symptoms, and from the clinical course and laboratory data the infant was diagnosed with CMA. The serum interleukin 5 (IL-5) (125 pg/mL) level in this patient was selectively elevated. However, serum levels of other T-helper 2 (Th2) cytokines (including IL-4 and IL-13), Th1 cytokines (including interferon γ), and proinflammatory cytokines (including tumor necrosis factor α) were not elevated. These findings suggest that, for this patient, IL-5 and eosinophils might have played a role in the development of neonatal CMA. Although this finding is reported from only 1 case, it highlights the need for serum IL-5 to be determined in more neonatal patients with CMA to further clarify the pathophysiology of this condition in the neonatal period.
Assuntos
Interleucina-5/sangue , Hipersensibilidade a Leite/sangue , Humanos , Recém-Nascido , MasculinoRESUMO
Cell adhesion molecule 1 (CADM1), a member of the immunoglobulin superfamily, mediates synaptic cell adhesion. Missense mutations in the CADM1 gene have been identified in autism spectrum disorder (ASD) patients. In the present study, we examined emotional behaviors, social behaviors and motor performances in Cadm1-knockout (KO) mice. Cadm1-KO mice showed increased anxiety-related behavior in open-field and light-dark transition tests. Social behaviors of Cadm1-KO mice were impaired in social interaction, resident-intruder and social memory/recognition tests. Furthermore, motor coordination and gait of Cadm1-KO mice were impaired in rotarod and footprint tests. Our study demonstrates that CADM1 plays roles in regulating emotional behaviors, social behaviors and motor performances, and that CADM1 has important implications for psychiatric disorders with disruptions in social behavior, such as autism.
Assuntos
Ansiedade/genética , Emoções , Imunoglobulinas/fisiologia , Proteínas de Membrana/fisiologia , Comportamento Social , Animais , Transtorno Autístico/genética , Molécula 1 de Adesão Celular , Moléculas de Adesão Celular , Imunoglobulinas/genética , Proteínas de Membrana/genética , Camundongos , Camundongos Knockout , Atividade Motora/genéticaRESUMO
BACKGROUND: Many Kawasaki disease (KD) patients have reached adulthood in Japan. The current status of adult patients who have giant coronary aneurysms with KD is not well understood. METHODS: Medical records of 48 KD patients (33 males and 15 females) with giant coronary aneurysms (maximum coronary artery internal diameter >8 mm) aged 20 years or over were retrospectively reviewed. RESULTS: The age of the patients at the diagnosis of KD ranged from 0.3 to 12.8 years (median 2.9 years) and the age of the patients in this review ranged from 20.0 to 33.1 years (median 25.2 years). During the follow-up period, the maximum coronary artery internal diameter ranged from 8.2 to 30.0 mm (median 10 mm). Giant coronary aneurysms progressed to coronary artery stenosis and/or complete occlusion in 34 (74%) of 46 patients. Coronary artery bypass graft surgery was performed in 9 (19%) of 48 patients. Myocardial infarction occurred in 14 (31%) of 45 patients. Other complications or problems occurred in 5 patients with angina pectoris, low left ventricular ejection fraction, ventricular tachycardia, hemorrhagic cerebral infarction, or thyroid carcinoma respectively. In the patients followed up, 4 dropped out. In addition, 1 patient succeeded in pregnancy and delivered a baby. CONCLUSIONS: Close attention should be paid to ventricular tachycardia in adult KD patients with giant coronary aneurysms, especially for those who have low left ventricular ejection fraction. To reduce the number of dropped out patients, it is important that the patients should be referred to a new doctor when they change their place of residence.
Assuntos
Aneurisma Coronário/epidemiologia , Síndrome de Linfonodos Mucocutâneos/epidemiologia , Adulto , Angina Pectoris/epidemiologia , Infarto Encefálico/epidemiologia , Ponte de Artéria Coronária/estatística & dados numéricos , Oclusão Coronária/epidemiologia , Estenose Coronária/epidemiologia , Feminino , Seguimentos , Humanos , Japão/epidemiologia , Masculino , Infarto do Miocárdio/epidemiologia , Gravidez , Estudos Retrospectivos , Volume Sistólico , Taquicardia Ventricular/epidemiologia , Neoplasias da Glândula Tireoide/epidemiologiaRESUMO
Osteoporosis-pseudoglioma syndrome (OPS; OMIM 259770) is an autosomal-recessive genetic disorder characterized by severe osteoporosis and visual disturbance from childhood. Biallelic mutations in the low-density lipoprotein receptor-related protein 5 gene (LRP5) have been frequently detected, while a subset of patients had only one or no detectable mutation. We report on the clinical and molecular findings of four unrelated Japanese patients with the syndrome. The four patients had typical skeletal and ocular phenotypes of OPS, namely severe juvenile osteoporosis and early-onset visual disturbance, with or without mental retardation. We undertook standard PCR-based sequencing for LRP5 and found four missense mutations (p.L145F, p.T244M, p.P382L, and p.T552M), one nonsense mutation (p.R1534X), and one splice site mutation (c.1584+1G>A) among four OPS patients. Although three patients had two heterozygous mutations, one had only one heterozygous splice site mutation. In this patient, RT-PCR from lymphocytic RNA demonstrated splice error resulting in 63-bp insertion between exons 7 and 8. Furthermore, the patient was found to have only mutated RT-PCR fragment, implying that a seemingly normal allele did not express LRP5 mRNA. We then conducted custom- designed oligonucleotide tiling microarray analyses targeted to a 600-kb genome region harboring LRP5 and discovered a 7.2-kb microdeletion encompassing exons 22 and 23 of LRP5. We found various types of LRP5 mutations, including an exon-level deletion that is undetectable by standard PCR-based mutation screening. Oligonucleotide tiling microarray seems to be a powerful tool in identifying cryptic structural mutations.
Assuntos
Glioma/genética , Proteínas Relacionadas a Receptor de LDL/genética , Mutação , Osteoporose/genética , Adolescente , Adulto , Sequência de Bases , Criança , Primers do DNA , Feminino , Humanos , Proteína-5 Relacionada a Receptor de Lipoproteína de Baixa Densidade , Masculino , Análise de Sequência com Séries de Oligonucleotídeos , Linhagem , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Deleção de Sequência , SíndromeRESUMO
This report describes the case of a 10-month-old boy who was diagnosed to have kaposiform hemangioendothelioma (KHE) with Kasabach-Merritt syndrome (KMS), which is a rare pediatric vascular tumor with a high mortality rate. Although both KHE with KMS were resistant to various therapies, such as oral prednisolone, sclerotherapy, and chemotherapy, repeated radiation therapy with methylprednisolone pulse therapy did reduce the volume of KHE and improved the symptoms of KMS. Unfortunately, a regrowth of KHE with KMS was observed 4 months after the cessation of treatment and the patient thereafter died from an intracranial hemorrhage and Pneumocystis carinii pneumonia, which is a complication related to repetitive radiation and steroid therapy. A histopathologic examination of autopsy specimens confirmed a diagnosis of KHE and immunohistologic staining was positive for vascular endothelial growth factor receptor (VEGFR)-2 and VEGFR-3. These findings may provide the rationale to further investigate the role of VEGFRs in the pathogenesis of KHE and also to elucidate its prognostic value, along with the application of inhibitors for VEGFRs for the treatment of refractory KHE.