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1.
Mutations in NSD1 are responsible for Sotos syndrome, but are not a frequent finding in other overgrowth phenotypes 总被引:6,自引:0,他引:6
Türkmen S Gillessen-Kaesbach G Meinecke P Albrecht B Neumann LM Hesse V Palanduz S Balg S Majewski F Fuchs S Zschieschang P Greiwe M Mennicke K Kreuz FR Dehmel HJ Rodeck B Kunze J Tinschert S Mundlos S Horn D 《European journal of human genetics : EJHG》2003,11(11):858-865
Recently, deletions encompassing the nuclear receptor binding SET-Domain 1 (NSD1) gene have been described as the major cause of Japanese patients with the Sotos syndrome, whereas point mutations have been identified in the majority of European Sotos syndrome patients. In order to investigate a possible phenotype-genotype correlation and to further define the predictive value of NSD1 mutations, we performed mutational analysis of the NSD1 gene in 20 patients and one familial case with Sotos syndrome, five patients with Weaver syndrome, six patients with unclassified overgrowth/mental retardation, and six patients with macrocephaly/mental retardation. We were able to identify mutations within the NSD1 gene in 18 patients and the familial case with Sotos syndrome (90%). The mutations (six nonsense, eight frame shifts, three splice site, one missense, one in-frame deletion) are expected to result in an impairment of NSD1 function. The best correlation between clinical assessment and molecular results was obtained for the Sotos facial gestalt in conjunction with overgrowth, macrocephaly, and developmental delay. In contrast to the high mutation detection rate in Sotos syndrome, none of the patients with Weaver syndrome, unclassified overgrowth/mental retardation and macrocephaly/mental retardation, harbored NSD1 mutations. We tested for large deletions by FISH analysis but were not able to identify any deletion cases. The results indicate that the great majority of patients with Sotos syndrome are caused by mutations in NSD1. Deletions covering the NSD1 locus were not found in the patients analyzed here. 相似文献
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A Jan 《Clinical genetics》2013,83(4):317-318
Alterations of the CIB2 calcium‐ and integrin‐binding protein cause Usher syndrome type 1J and non‐syndromic deafness DFNB48 Riazuddin et al. (2012) Nature Genetics 44(11):1265–1271 相似文献
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Mutations in the KCNQ4 gene are responsible for autosomal dominant deafness in four DFNA2 families. 总被引:9,自引:0,他引:9
P J Coucke P Van Hauwe P M Kelley H Kunst I Schatteman D Van Velzen J Meyers R J Ensink M Verstreken F Declau H Marres K Kastury S Bhasin W T McGuirt R J Smith C W Cremers P Van de Heyning P J Willems S D Smith G Van Camp 《Human molecular genetics》1999,8(7):1321-1328
We have previously found linkage to chromosome 1p34 in five large families with autosomal dominant non-syndromic hearing impairment (DFNA2). In all five families, the connexin31 gene ( GJB3 ), located at 1p34 and responsible for non-syndromic autosomal dominant hearing loss in two small Chinese families, has been excluded as the responsible gene. Recently, a fourth member of the KCNQ branch of the K+channel family, KCNQ4, has been cloned. KCNQ4 was mapped to chromosome 1p34 and a single mutation was found in three patients from a small French family with non-syndromic autosomal dominant hearing loss. In this study, we have analysed the KCNQ4 gene for mutations in our five DFNA2 families. Missense mutations altering conserved amino acids were found in three families and an inactivating deletion was present in a fourth family. No KCNQ4 mutation could be found in a single DFNA2 family of Indonesian origin. These results indicate that at least two and possibly three genes responsible for hearing impairment are located close together on chromosome 1p34 and suggest that KCNQ4 mutations may be a relatively frequent cause of autosomal dominant hearing loss. 相似文献
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《Genetics in medicine》2016,18(4):378-385
PurposeAutism spectrum disorders are associated with defects in social response and communication that often occur in the context of intellectual disability. Rett syndrome is one example in which epilepsy, motor impairment, and motor disturbance may co-occur. Mutations in histone demethylases are known to occur in several of these syndromes. Herein, we aimed to identify whether mutations in the candidate histone demethylase JMJD1C (jumonji domain containing 1C) are implicated in these disorders.MethodsWe performed the mutational and functional analysis of JMJD1C in 215 cases of autism spectrum disorders, intellectual disability, and Rett syndrome without a known genetic defect.ResultsWe found seven JMJD1C variants that were not present in any control sample (~ 6,000) and caused an amino acid change involving a different functional group. From these, two de novo JMJD1C germline mutations were identified in a case of Rett syndrome and in a patient with intellectual disability. The functional study of the JMJD1C mutant Rett syndrome patient demonstrated that the altered protein had abnormal subcellular localization, diminished activity to demethylate the DNA damage-response protein MDC1, and reduced binding to MECP2. We confirmed that JMJD1C protein is widely expressed in brain regions and that its depletion compromises dendritic activity.ConclusionsOur findings indicate that mutations in JMJD1C contribute to the development of Rett syndrome and intellectual disability. 相似文献
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Mutations of the UMOD gene are responsible for medullary cystic kidney disease 2 and familial juvenile hyperuricaemic nephropathy 总被引:16,自引:1,他引:15
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Hart TC Gorry MC Hart PS Woodard AS Shihabi Z Sandhu J Shirts B Xu L Zhu H Barmada MM Bleyer AJ 《Journal of medical genetics》2002,39(12):882-892
Introduction: Medullary cystic kidney disease 2 (MCKD2) and familial juvenile hyperuricaemic nephropathy (FJHN) are both autosomal dominant renal diseases characterised by juvenile onset of hyperuricaemia, gout, and progressive renal failure. Clinical features of both conditions vary in presence and severity. Often definitive diagnosis is possible only after significant pathology has occurred. Genetic linkage studies have localised genes for both conditions to overlapping regions of chromosome 16p11-p13. These clinical and genetic findings suggest that these conditions may be allelic. 相似文献
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Tomoeda K Awata H Matsuura T Matsuda I Ploechl E Milovac T Boneh A Scott CR Danks DM Endo F 《Molecular genetics and metabolism》2000,71(3):506-510
The enzyme 4-hydroxyphenylpyruvic acid dioxygenase (HPD) catalyzes the reaction of 4-hydroxyphenylpyruvic acid to homogentisic acid in the tyrosine catabolism pathway. A deficiency in the catalytic activity of HPD may lead to tyrosinemia type III, an autosomal recessive disorder characterized by elevated levels of blood tyrosine and massive excretion of tyrosine derivatives into urine. It has been postulated that hawkinsinuria, an autosomal dominant disorder characterized by the excretion of 'hawkinsin,' may also be a result of HPD deficiency. Hawkinsin is a sulfur amino acid identified as (2-l-cystein-S-yl, 4-dihydroxycyclohex-5-en-1-yl)acetic acid. Patients with hawkinsinuria excrete this metabolite in their urine throughout their life, although symptoms of metabolic acidosis and tyrosinemia improve in the first year of life. We performed analyses of the HPD gene in a patient with tyrosinemia type III and two unrelated patients with hawkinsinuria. A homozygous missense mutation predicting an Ala to Val change at codon 268 (A268V) in the HPD gene was found in the patient with tyrosinemia type III. A heterozygous missense mutation predicting an Ala to Thr change at codon 33 (A33T) was found in the same HPD gene in the two patients with hawkinsinuria. These findings support the hypothesis that alterations in the structure and activity of HPD are causally related to two different metabolic disorders, tyrosinemia type III and hawkinsinuria. 相似文献
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Lisenka ELM Vissers Monica Bonetti Jeroen Paardekooper Overman Willy M Nillesen Suzanna G M Frints Joep de Ligt Giuseppe Zampino Ana Justino José C Machado Marga Schepens Han G Brunner Joris A Veltman Hans Scheffer Piet Gros José L Costa Marco Tartaglia Ineke van der Burgt Helger G Yntema Jeroen den Hertog 《European journal of human genetics : EJHG》2015,23(3):317-324
Noonan syndrome (NS) is a developmental disorder characterized by short stature, facial dysmorphisms and congenital heart defects. To date, all mutations known to cause NS are dominant, activating mutations in signal transducers of the RAS/mitogen-activated protein kinase (MAPK) pathway. In 25% of cases, however, the genetic cause of NS remains elusive, suggesting that factors other than those involved in the canonical RAS/MAPK pathway may also have a role. Here, we used family-based whole exome sequencing of a case–parent trio and identified a de novo mutation, p.(Arg802His), in A2ML1, which encodes the secreted protease inhibitor α-2-macroglobulin (A2M)-like-1. Subsequent resequencing of A2ML1 in 155 cases with a clinical diagnosis of NS led to the identification of additional mutations in two families, p.(Arg802Leu) and p.(Arg592Leu). Functional characterization of these human A2ML1 mutations in zebrafish showed NS-like developmental defects, including a broad head, blunted face and cardiac malformations. Using the crystal structure of A2M, which is highly homologous to A2ML1, we identified the intramolecular interaction partner of p.Arg802. Mutation of this residue, p.Glu906, induced similar developmental defects in zebrafish, strengthening our conclusion that mutations in A2ML1 cause a disorder clinically related to NS. This is the first report of the involvement of an extracellular factor in a disorder clinically related to RASopathies, providing potential new leads for better understanding of the molecular basis of this family of developmental diseases. 相似文献
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Marie Vincent Corinne Collet Alain Verloes Laetitia Lambert Christian Herlin Catherine Blanchet Elodie Sanchez Séverine Drunat Jacqueline Vigneron Jean-Louis Laplanche Jacques Puechberty Pierre Sarda David Geneviève 《European journal of human genetics : EJHG》2014,22(1):52-56
Mandibulofacial dysostosis is part of a clinically and genetically heterogeneous group of disorders of craniofacial development, which lead to malar and mandibular hypoplasia. Treacher Collins syndrome is the major cause of mandibulofacial dysostosis and is due to mutations in the TCOF1 gene. Usually patients with Treacher Collins syndrome do not present with intellectual disability. Recently, the EFTUD2 gene was identified in patients with mandibulofacial dysostosis associated with microcephaly, intellectual disability and esophageal atresia. We report on two patients presenting with mandibulofacial dysostosis characteristic of Treacher Collins syndrome, but associated with unexpected intellectual disability, due to a large deletion encompassing several genes including the TCOF1 gene. We discuss the involvement of the other deleted genes such as CAMK2A or SLC6A7 in the cognitive development delay of the patients reported, and we propose the systematic investigation for 5q32 deletion when intellectual disability is associated with Treacher Collins syndrome. 相似文献
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We report new mutations in exon 9 of the WT1 gene that did not alter the ratio of +/- KTS splice isoforms in two unrelated patients with Frasier syndrome (FS). The mutation of intron 9 inducing defective alternative splicing was reported to be responsible for this syndrome. The mutations found in our cases occurred in the same exon of the WT1 gene as detected in Denys-Drash syndrome (DDS) and could not be explained by the previously proposed mechanism. The results suggest that the two syndromes originate from the same WT1 gene abnormality. From a molecular biological point of view, we concluded that the two diseases were not separable, and that FS should be included as an atypical form of DDS. 相似文献
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Mutations in the genome of porcine reproductive and respiratory syndrome virus responsible for the attenuation phenotype 总被引:16,自引:0,他引:16
Allende R Kutish GF Laegreid W Lu Z Lewis TL Rock DL Friesen J Galeota JA Doster AR Osorio FA 《Archives of virology》2000,145(6):1149-1161
Summary. Although live-attenuated vaccines have been used for some time to control clinical symptoms of the porcine reproductive and
respiratory syndrome (PRRS), the molecular bases for the attenuated phenotype remain unclear. We had previously determined
the genomic sequence of the pathogenic PRRSV 16244B. Limited comparisons of the structural protein coding sequence of an attenuated
vaccine strain have shown 98% homology to the pathogenic 16244B. Here we have confirmed the attenuated phenotype and determined
the genomic sequence of that attenuated PRRSV vaccine and compared it to its parental VR-2332 and the 16244B strains. The
attenuated vaccine sequence was colinear with that of the strain 16244B sequence containing no gaps and 212 substitutions
over 15,374 determined nucleotide sequence. We identified nine amino acid changes distributed in Nsp1β, Nsp2, Nsp10, ORF2,
ORF3, ORF5 and ORF6. These changes may provide the molecular bases for the observed attenuated phenotype.
Received August 28, 1999 Accepted December 16, 1999 相似文献
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Mutations linked to the pro alpha 2(I) collagen gene are responsible for several cases of osteogenesis imperfecta type I. 总被引:6,自引:1,他引:6
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We have analysed six South African families with osteogenesis imperfecta type I using three DNA polymorphisms associated with the pro alpha 2(I) collagen gene. In four of these families linkage of the pro alpha 2(I) gene and the osteogenesis imperfecta phenotype was suggested, whereas in the remaining two families there was a lack of linkage. No distinct correlation could be made between the phenotypic features of the families studied and linkage or lack of linkage to the pro alpha 2(I) gene. Two different haplotypes were found to be associated with the mutant pro alpha 2(I) alleles. These findings suggest that molecular heterogeneity exists within osteogenesis imperfecta type I and that in a significant proportion of cases the defect is linked to the pro alpha 2(I) gene. 相似文献
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Tanya Girard Denis Gaucher Mohamed El-Far Gaëlle Breton Rafick-Pierre Sékaly 《Immunology letters》2014
CD86 and CD80, the ligands for the co-stimulatory molecules CD28 and CTLA-4, are members of the Ig superfamily. Their structure includes Ig variable-like (IgV) domains, Ig constant-like (IgC) domains and intracellular domains. Although crystallographic studies have clearly identified the IgV domain to be responsible for receptor interactions, earlier studies suggested that both Ig domains are required for full co-signaling function. Herein, we have used deletion and chimeric human CD80 and CD86 molecules in co-stimulation assays to study the impact of the multimeric state of IgV and IgC domains on receptor binding properties and on co-stimulatory function in a peptide-specific T cell activation model. We report for the first time the presence of CD80 dimers and CD86 monomers in living cells. Moreover, we show that the IgC domain of both molecules inhibits multimer formation and greatly affects binding to the co-receptors CD28 and CTLA-4. Finally, both IgC and intracellular domains are required for full co-signaling function. These findings reveal the distinct but complementary roles of CD80 and CD86 IgV and IgC domains in T cell activation. 相似文献
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Mutations in the carboxyl terminal region of E2 glycoprotein of classical swine fever virus are responsible for viral attenuation in swine 总被引:4,自引:0,他引:4
Risatti GR Holinka LG Fernandez Sainz I Carrillo C Kutish GF Lu Z Zhu J Rock DL Borca MV 《Virology》2007,364(2):371-382
We have previously reported [Risatti, G.R., Borca, M.V., Kutish, G.F., Lu, Z., Holinka, L.G., French, R.A., Tulman, E.R., Rock, D.L. 2005a. The E2 glycoprotein of classical swine fever virus is a virulence determinant in swine. J. Virol. 79, 3787-3796] that chimeric virus 319.1v containing the E2 glycoprotein gene from Classical Swine Fever Virus (CSFV) vaccine strain CS with the genetic background of highly virulent CSFV strain Brescia (BICv) was markedly attenuated in pigs. To identify the amino acids mediating 319.1v attenuation a series of chimeric viruses containing CS E2 residues in the context of the Brescia strain were constructed. Chimera 357v, containing CS E2 residues 691 to 881 of CSFV polyprotein was virulent, while chimera 358v, containing CS E2 residues 882 to 1064, differing in thirteen amino acids from BICv, was attenuated in swine. Single or double substitutions of those amino acids in BICv E2 to CS E2 residues did not affect virulence. Groups of amino acids were then substituted in BICv E2 to CS E2 residues. Mutant 32v, with six substitutions between residues 975 and 1059, and mutant 33v, with six substitutions between 955 and 994, induced disease indistinguishable from BICv. Mutant 31v, with seven substitutions between residues 882 and 958, induced a delayed onset of lethal disease. Amino acids abrogating BICv virulence were then determined by progressively introducing six CS residues into 31v. Mutant 39v, containing nine residue substitutions, was virulent. Mutant 40v, containing ten residue substitutions, induced mild disease. Mutant 42v, containing twelve substitutions, and mutant 43v, with an amino acid composition identical to 358v, were attenuated in swine indicating that all substitutions were necessary for attenuation of the highly virulent strain Brescia. Importantly, 358v protected swine from challenge with virulent BICv at 3 and 28 days post-infection. 相似文献
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Schell Ute; Hehr Andreas; Feldman George J.; Robin Nathaniel H.; Zackai Elaine H.; de Die-Smulders Christine; Viskochil David H.; Stewart Janet M.; Wolff Gerhard; Ohashi Hirofumi; Price R. Arlen; Cohen M.Michael Jr.; Muenke Maximilian 《Human molecular genetics》1995,4(3):323-328
Pfeifter syndrome (PS) is an autosomal dominant skeletal disorderwhich affects the bones of the skull, hands and feet. Previously,we have mapped PS in a subset of families to chromosome 8cenby linkage analysis and demonstrated a common mutation in thefibroblast growth factor receptor-1 (FGFR1) gene in the linkedfamilies. Here we report a second locus for PS on chromosome10q25, and present evidence that mutations in the fibroblastgrowth factor receptor-2 (FGFR2) gene on 10q25 cause PS in anadditional subset of familial and sporadic cases. Three differentpoint mutations in FGFR2, which alter the same acceptor splicesite of exon B, were observed in both sporadic and familialPS. In addition, a T to C transition in exon B predicting acysteine to arginine substitution was identified in three sporadicPS individuals. Interestingly, this T to C change is identicalto a mutation in FGFR2 previously reported in Crouzon syndrome,a phenotypically similar disorder but one lacking the hand andfoot anomalies seen in PS. Our results highlight the geneticheterogeneity in PS and suggest that the molecular data willbe an important complement to the clinical phenotype in definingcraniosynostosis syndromes. 相似文献
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Ferguson PJ Chen S Tayeh MK Ochoa L Leal SM Pelet A Munnich A Lyonnet S Majeed HA El-Shanti H 《Journal of medical genetics》2005,42(7):551-557
Background: Majeed syndrome is an autosomal recessive, autoinflammatory disorder characterised by chronic recurrent multifocal osteomyelitis and congenital dyserythropoietic anaemia. The objectives of this study were to map, identify, and characterise the Majeed syndrome causal gene and to speculate on its function and role in skin and bone inflammation. 相似文献