共查询到20条相似文献,搜索用时 24 毫秒
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Whalen S Héron D Gaillon T Moldovan O Rossi M Devillard F Giuliano F Soares G Mathieu-Dramard M Afenjar A Charles P Mignot C Burglen L Van Maldergem L Piard J Aftimos S Mancini G Dias P Philip N Goldenberg A Le Merrer M Rio M Josifova D Van Hagen JM Lacombe D Edery P Dupuis-Girod S Putoux A Sanlaville D Fischer R Drévillon L Briand-Suleau A Metay C Goossens M Amiel J Jacquette A Giurgea I 《Human mutation》2012,33(1):64-72
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《European journal of medical genetics》2017,60(11):565-571
Pitt-Hopkins syndrome is a neurodevelopmental disorder characterized by severe intellectual disability and a distinctive facial gestalt. It is caused by haploinsufficiency of the TCF4 gene. The TCF4 protein has different functional domains, with the NLS (nuclear localization signal) domain coded by exons 7–8 and the bHLH (basic Helix-Loop-Helix) domain coded by exon 18. Several alternatively spliced TCF4 variants have been described, allowing for translation of variable protein isoforms. Typical PTHS patients have impairment of at least the bHLH domain. To which extent impairment of the remaining domains contributes to the final phenotype is not clear. There is recent evidence that certain loss-of-function variants disrupting TCF4 are associated with mild ID, but not with typical PTHS. We describe a frameshift-causing partial gene deletion encompassing exons 4–6 of TCF4 in an adult patient with mild ID and nonspecific facial dysmorphisms but without the typical features of PTHS, and a c.520C > T nonsense variant within exon 8 in a child presenting with a severe phenotype largely mimicking PTHS, but lacking the typical facial dysmorphism. Investigation on mRNA, along with literature review, led us to suggest a preliminary phenotypic map of loss-of-function variants affecting TCF4.An intragenic phenotypic map of loss-of-function variants in TCF4 is suggested here for the first time: variants within exons 1–4 and exons 4–6 give rise to a recurrent phenotype with mild ID not in the spectrum of Pitt-Hopkins syndrome (biallelic preservation of both the NLS and bHLH domains); variants within exons 7–8 cause a severe phenotype resembling PTHS but in absence of the typical facial dysmorphism (impairment limited to the NLS domain); variants within exons 9–19 cause typical Pitt-Hopkins syndrome (impairment of at least the bHLH domain). Understanding the TCF4 molecular syndromology can allow for proper nosology in the current era of whole genomic investigations. 相似文献
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Marangi G Ricciardi S Orteschi D Lattante S Murdolo M Dallapiccola B Biscione C Lecce R Chiurazzi P Romano C Greco D Pettinato R Sorge G Pantaleoni C Alfei E Toldo I Magnani C Bonanni P Martinez F Serra G Battaglia D Lettori D Vasco G Baroncini A Daolio C Zollino M 《American journal of medical genetics. Part A》2011,155(7):1536-1545
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Marangi G Ricciardi S Orteschi D Tenconi R Monica MD Scarano G Battaglia D Lettori D Vasco G Zollino M 《American journal of medical genetics. Part A》2012,(7):1604-1611
Pitt-Hopkins syndrome (PTHS) is an emerging condition characterized by severe intellectual disability (ID), typical facial gestalt, and additional features, such as breathing abnormalities. Because of the overlapping phenotype of severe ID with absent speech, epilepsy, microcephaly, large mouth, and constipation, differential diagnosis of PTHS with respect to Angelman, Rett, and Mowat-Wilson syndromes represents a relevant clinical issue, and many patients are currently undergoing genetic tests for different conditions that are assumed to fall within the PTHS clinical spectrum. During a search for TCF4 mutations in 78 patients with a suspected PTHS, haploinsufficiency of TCF4 was identified in 18. By evaluating clinical features of patients with a proven TCF4 mutation with those of patients without, we noticed that, in addition to the typical facial gestalt, the PTHS phenotype results from the various combination of the following characteristics: ID with severe speech impairment, normal growth parameters at birth, postnatal microcephaly, breathing abnormalities, motor incoordination, ocular anomalies, constipation, seizures, typical behavior, and subtle brain abnormalities. On the basis of these observations, here we propose a clinically based score system as useful tool for driving a first choice molecular test for PTHS. This scoring system is also proposed for a clinically based diagnosis of PTHS in absence of a proven TCF4 mutation. 相似文献
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D Tserpelis EEJ Smeets TJ Kranenburg‐de Koning KH de Waal C Zweier A Rauch RCM Hennekam MJ Blok CTRM Schrander‐Stumpel 《Clinical genetics》2013,83(1):73-77
Steinbusch CVM, van Roozendaal KEP, Tserpelis D, Smeets EEJ, Kranenburg‐de Koning TJ, de Waal KH, Zweier C, Rauch A, Hennekam RCM, Blok MJ, Schrander‐Stumpel CTRM. Somatic mosaicism in a mother of two children with Pitt–Hopkins syndrome. Pitt–Hopkins syndrome (PTHS) is a neurodevelopmental disorder characterized by intellectual disability, unusual face and breathing abnormalities and can be caused by haploinsufficiency of TCF4. The majority of cases are sporadic. Somatic mosaicism was reported infrequently. We report on a proband with typical manifestations of PTHS and his younger brother with a less striking phenotype. In both, a heterozygous frameshift mutation (c.1901_1909delinsA, p.Ala634AspfsX67) was found in exon 19 of TCF4. The same mutation was found at low levels in DNA extracted from the mother's blood, urine and saliva. This report of familial recurrence with somatic mosaicism in a healthy mother has important consequences for genetic counseling. We suggest careful studies in parents of other patients with PTHS to determine the frequency of germline and somatic mosaicism for TCF4 mutations. 相似文献
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Marlies J. Valstar Aida M. Bertoli‐Avella Marja W. Wessels George J.G. Ruijter Bianca de Graaf Renske Olmer Peter Elfferich Sanne Neijs Roxana Kariminejad Fatih Suheyl Ezgü Aysegul Tokatli Barbara Czartoryska Ad N. Bosschaart Feikje van den Bos‐Terpstra Hugues Puissant Friederike Bürger Heymut Omran D. Eckert Mirella Filocamo Emil Simeonov Patrick J. Willems Ron A. Wevers Martinus F. Niermeijer Dicky J.J. Halley Ben J.H.M. Poorthuis Otto P. van Diggelen 《Human mutation》2010,31(5):E1348-E1360
Mucopolysaccharidosis III D (Sanfilippo disease type D, MPS IIID) is a rare autosomal recessive lysosomal storage disorder previously described in only 20 patients. MPS IIID is caused by a deficiency of N‐acetylglucosamine‐6‐sulphate sulphatase (GNS), one of the enzymes required for the degradation of heparan sulphate. So far only seven mutations in the GNS gene have been reported. The clinical phenotype of 12 new MPS IIID patients from 10 families was studied. Mutation analysis of GNS was performed in 16 patients (14 index cases). Clinical signs and symptoms of the MPS IIID patients appeared to be similar to previously described patients with MPS III. Early development was normal with onset of behavioral problems around the age of 4 years, followed by developmental stagnation, deterioration of verbal communication and subsequent deterioration of motor functions. Sequence analysis of the coding regions of the gene encoding GNS (GNS) resulted in the identification of 15 novel mutations: 3 missense mutations, 1 nonsense mutation, 4 splice site mutations, 3 frame shift mutations, 3 large deletions and 1 in‐frame small deletion. They include the first missense mutations and a relatively high proportion of large rearrangements, which warrants the inclusion of quantitative techniques in routine mutation screening of the GNS gene. © 2010 Wiley‐Liss, Inc. 相似文献
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TBK1 Mutation Spectrum in an Extended European Patient Cohort with Frontotemporal Dementia and Amyotrophic Lateral Sclerosis
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Sara Van Mossevelde Federica Perrone Lubina Dillen Bavo Heeman Veerle Bäumer Sebastiaan Engelborghs Jan De Bleecker Jonathan Baets Ellen Gelpi Ricardo Rojas‐García Jordi Clarimón Alberto Lleó Janine Diehl‐Schmid Panagiotis Alexopoulos Robert Perneczky Matthis Synofzik Jennifer Just Ludger Schöls Caroline Graff Håkan Thonberg Barbara Borroni Alessandro Padovani Albena Jordanova Stayko Sarafov Ivailo Tournev Alexandre de Mendonça Gabriel Miltenberger‐Miltényi Frederico Simões do Couto Alfredo Ramirez Frank Jessen Michael T. Heneka Estrella Gómez‐Tortosa Adrian Danek Patrick Cras Rik Vandenberghe Peter De Jonghe Peter P. De Deyn Kristel Sleegers Marc Cruts Christine Van Broeckhoven Silvia Testi 《Human mutation》2017,38(3):297-309
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Functional implications of the spectrum of mutations found in 234 cases with X-linked juvenile retinoschisis. The Retinoschisis Consortium 总被引:1,自引:0,他引:1
《Human molecular genetics》1998,7(7):1185-1192
X-linked retinoschisis (XLRS) is the most common cause of juvenile macular
degeneration in males, resulting in vision loss early in life. The gene
involved in XLRS was identified recently. It encodes a protein with a
disoidin domain, suggested to be involved in cell-cell interactions. We
have screened the gene for mutations in 234 familial and sporadic
retinoschisis cases and identified 82 different mutations in 214 (91%).
Thirty one mutations were found more than once, i.e. 2-10 times, with the
exception of the 214G-->A mutation which was found in 34 apparently
unrelated cases. The origin of the patients, the linkage data and the site
of the mutations (mainly CG dinucleotides) indicate that most recurrent
mutations had independent origins and thus suggest the existence of a
significant new mutation rate in XLRS1. The mutations identified cover the
entire spectrum, from small intra-genic deletions (7%), to nonsense (6%),
missense (75%), small frameshifting insertions/deletions (6%) and splice
site mutations (6%). Since, regardless of the mutation type, no females
with a typical RS phenotype were identified, RS seems to be caused by
loss-of-function mutations only. Mutations occurred non-randomly, with
hotspots at several CG dinucleotides and a C6stretch. Exons 1-3 contained
few, mainly translation-truncating mutations, arguing against an important
functional role for this segment of the protein. Exons 4-6, encoding the
discoidin domain, contained most, mainly missense mutations. An alignment
of 32 discoidin domain proteins was constructed to reveal the consensus
sequence and to deduce the functional importance of the missense mutations
identified. The mutation analysis revealed a high preponderance of
mutations involving or creating cysteine residues, pointing to sites
important for the tertiary folding and/or protein function, and highlights
several amino acids which may be involved in XLRS1-specific protein-protein
interactions. Despite the enormous mutation heterogeneity, patients have
relatively uniform clinical manifestations although with great
intra-familial variation in age at onset and progression.
相似文献
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肺腺癌中p16基因外显子2的突变分析 总被引:3,自引:0,他引:3
为了解肺腺癌p16基因外显子2的突变情况,应用聚合酶链反应(PCR)及PCR双链DNA循环测序技术分析了22例肺腺癌中的p16基因,结果显示:22例肺腺癌中存在2例纯合缺失,3例点突变。其中病例1密码子56由CTG→CAG的突变,编码的氨基酸由亮氨酸变为谷氨酰胺;病例12密码子121由TAC→TGC的突变,编码的氨基酸由酪氨酸变为半胱氨酸;病例10密码子80由GAG→AAG的突变,编码的氨基酸由谷氨酸变为赖氨酸,同时这例密码子79存在一个由CGG→AGG的同义突变。另外还发现1例由单碱基缺失导致的移码突变。p16基因在22例肺腺癌中纯合缺失频率为9.1%,基因突变频率为27.3%。可见,多重肿瘤抑制基因p16与肺腺癌的发生发展密切相关并在其演进过程中起着一定的作用。 相似文献
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INK4a/ARF locus alterations in human non-Hodgkin's lymphomas mainly occur in tumors with wild-type p53 gene 总被引:3,自引:0,他引:3
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Pinyol M Hernández L Martínez A Cobo F Hernández S Beà S López-Guillermo A Nayach I Palacín A Nadal A Fernández PL Montserrat E Cardesa A Campo E 《The American journal of pathology》2000,156(6):1987-1996
INK4a/ARF locus codes for two different proteins, p16(INK4a) and p14(ARF), involved in cell cycle regulation. p14(ARF) is considered an upstream regulator of p53 function. To determine the role of these genes in the pathogenesis of human non-Hodgkin's lymphomas we have analyzed exon 1beta, 1alpha, and 2 of the INK4a/ARF locus and p53 gene aberrations in 97 tumors previously characterized for p16(INK4a) alterations. p53 alterations were detected in four of 51 (8%) indolent lymphomas but in 15 of 46 (33%) aggressive tumors. Inactivation of p14(ARF) was always associated with p16(INK4a) alterations. Exon 1beta was concomitantly deleted with exon 1alpha and 2 in eight tumors. One additional lymphoblastic lymphoma showed deletion of exon 1alpha and 2 but retained exon 1beta. No mutations were detected in exon 1alpha and 1beta in any case. Two of the three mutations detected in exon 2 caused a nonsense mutation in the p16(INK4a) reading frame and a missense mutation in the ARF reading frame involving the nucleolar transport domain of the protein. The third mutation was a missense mutation in the p16(INK4a) reading frame, but it was outside the coding region of p14(ARF). Aggressive lymphomas with p14(ARF) inactivation and p53 wild type showed a significantly lower p53 protein expression than tumors with no alteration in any of these genes. In this series of tumors, inactivation of the INK4a/ARF locus mainly occurred in tumors with a wild-type p53 gene because only two lymphomas showed simultaneous aberrations in these genes. Tumors with concomitant alterations of p16(INK4a) and p14(ARF)/p53 genes seem to exhibit a worse clinical behavior than lymphomas with no alterations or isolated inactivation of any of these genes. These findings indicate that p14(ARF) genetic alterations occur in a subset of aggressive NHLs, but they are always associated with p16(INK4a) aberrations. Concomitant disruption of p16(INK4a) and p14(ARF)/p53 regulatory pathways may have a cooperative effect in the progression of these tumors. 相似文献
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Proof of a non-functional muscle chloride channel in recessive myotonia congenita (Becker) by detection of a 4 base pair deletion 总被引:2,自引:0,他引:2
Heine Ronald; George Alfred L. Jr; Pika Ursula; Deymeer Feza; Rudel Reinhardt; Lehmann-Horn Frank 《Human molecular genetics》1994,3(7):1123-1128
Recessive myotonia congenlta (Becker) is genetically linkedto HUMCLC, the gene encoding the muscular chloride channel,localized on chromosome 7q35. Three point mutations have sofar been reported In HUMCLC, one causing recessive Becker-typemyotonia, the others causing the clinically similar Thomsen-typemyotonia, which is Inherited as a dominant trait. We reporta homozygous patient having a 4 base pair deletion in HUMCLCthat shifts the reading frame and causes early stop codons,thus destroying the gene's coding potential for several membrane-spanningdomains. In addition, we report a patient homozygous for a novelpoint mutation located at the extracellular side of the firstmembrane-spanning domain that causes removal of a negative charge(aspartic acid-136-glyclne). Both mutations lead to the recessivetype of myotonia congenita. Since the patient having the deletionpresents less severe clinical myotonia than the patient carryingthe missense mutation, it seems that the absence or truncationof the channel protein may disturb muscle fibre function lessthan the substitution of a single amino acid. 相似文献
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Morphopoietic switch mutations of bacteriophage P2. 总被引:7,自引:0,他引:7
During the growth of bacteriophage P4, for which the genome of bacteriophage P2 is needed as helper, the decision whether to make large, P2 size, heads or small, P4 size, heads depends on the size-directing function of P4's sid gene and on P2's "sid responsiveness." P2 mutants (=P2 sir) impaired in their response to P4's sid function are readily obtainable as one class of P2 plaque formers selected on certain P4 cl plasmid lysogens. We describe nine P2 sir mutants of independent origin. For eight we could assign their sir mutation to P2 gene N, which encodes the major capsid protein. DNA sequencing indicated an open reading frame of 357 codons for gene N and showed these sir mutations to affect only four codons within a 38-codon segment in the middle of N. Seven mutations are missense mutations (three of them identical); one is a deletion of one codon. There seems to be a correlation between the phenotypic "strength" of the sir mutations and the type of amino acid replacement by missense mutations. Although the weakest mutation, sir7, could not yet be assigned to any P2 gene, it appears clear from this work that P2's N gene product is the major (or only) target of P4's Sid gene function. 相似文献