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1.
Three novel GJB2 (connexin 26) variants associated with autosomal dominant syndromic and nonsyndromic hearing loss
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Desiree DeMille Oliver H. Tam Janice C. Palumbos Heather J. Stalker Rong Mao Roberto T. Zori David H. Viskochil Albert H. Park John C. Carey 《American journal of medical genetics. Part A》2018,176(4):945-950
Connexin 26 (Cx26), encoded by the GJB2 gene, is a key protein involved in the formation of gap junctions in epithelial organs including the inner ear and palmoplantar epidermis. Pathogenic variants in GJB2 are responsible for approximately 50% of inherited sensorineural deafness. The majority of these variants are associated with autosomal recessive inheritance; however, rare reports of dominantly co‐segregating variants have been published. Since we began offering GJB2 testing in 2003, only about 2% of detected GJB2 variants from our laboratory have been classified as dominant. Here we report three novel dominant GJB2 variants (p.Thr55Ala, p.Gln57_Pro58delinsHisSer, and p.Trp44Gly); two associated with syndromic sensorineural hearing loss and one with nonsyndromic hearing loss. In the kindred with the p.Thr55Ala variant, the proband and his father present with only leukonychia as a cutaneous finding of their syndromic hearing loss. This phenotype has been previously documented in conjunction with palmoplantar hyperkeratosis, but isolated leukonychia is a novel finding likely associated with the unique threonine to alanine change at codon 55 (other variants at this codon have been reported in cases of nonsyndromic hearing loss). This report contributes to the short list of GJB2 variants associated with autosomal dominant hearing loss, highlights the variability of skin and nail findings associated with such cases, and illustrates the occurrence of both syndromic and nonsyndromic presentations with changes in the same gene. 相似文献
2.
Leila Youssefian Hassan Vahidnezhad Amir Hossein Saeidian Hamidreza Mahmoudi Razieh Karamzadeh Ariana Kariminejad Jianhe Huang Leping Li Thomas F. Jannace Paolo Fortina Sirous Zeinali Thomas W. White Jouni Uitto 《Human mutation》2019,40(2):217-229
Ichthyosis follicularis, a distinct cutaneous entity reported in combination with atrichia, and photophobia has been associated with mutations in MBTPS2. We sought the genetic cause of a novel syndrome of ichthyosis follicularis, bilateral severe sensorineural hearing loss and punctate palmoplantar keratoderma in two families. We performed whole exome sequencing on three patients from two families. The pathogenicity and consequences of mutations were studied in the Xenopus oocyte expression system and by molecular modeling analysis. Compound heterozygous mutations in the GJB2 gene were discovered: a pathogenic c.526A>G; p.Asn176Asp, and a common frameshift mutation, c.35delG; p.Gly12Valfs*2. The p.Asn176Asp missense mutation was demonstrated to significantly reduce the cell–cell gap junction channel activity and increase the nonjunctional hemichannel activity in the Xenopus oocyte expression system. Molecular modeling analyses of the mutant Cx26 protein revealed significant changes in the structural characteristics and electrostatic potential of the Cx26, either in hemichannel or gap junction conformation. Thus, association of a new syndrome of an autosomal recessive disorder of ichthyosis follicularis, bilateral severe sensorineural hearing loss and punctate palmoplantar keratoderma with mutations in GJB2, expands the phenotypic spectrum of the GJB2‐associated disorders. The findings attest to the complexity of the clinical consequences of different mutations in GJB2. 相似文献
3.
A novel C202F mutation in the connexin26 gene (GJB2) associated with autosomal dominant isolated hearing loss
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Morlé L Bozon M Alloisio N Latour P Vandenberghe A Plauchu H Collet L Edery P Godet J Lina-Granade G 《Journal of medical genetics》2000,37(5):368-370
Mutations in the GJB2 gene encoding connexin26 (CX26) account for up to 50% of cases of autosomal recessive hearing loss. In contrast, only one GJB2 mutation has been reported to date in an autosomal dominant form of isolated prelingual hearing loss. We report here a novel heterozygous 605G→T mutation in GJB2 in all affected members of a large family with late childhood onset of autosomal dominant isolated hearing loss. The resulting C202F substitution, which lies in the fourth (M4) transmembrane domain of CX26, may impair connexin oligomerisation. Finally, our study suggests that GJB2 should be screened for heterozygous mutations in patients with autosomal dominant isolated hearing impairment, whatever the severity of the disease.
Keywords: C202F mutation; connexin26 gene (GJB2); autosomal dominant hearing loss 相似文献
Keywords: C202F mutation; connexin26 gene (GJB2); autosomal dominant hearing loss 相似文献
4.
A connexin 26 mutation causes a syndrome of sensorineural hearing loss and palmoplantar hyperkeratosis (MIM 148350) 总被引:5,自引:0,他引:5
We report a missense mutation in the connexin 26 gene (GJB2) in a family with an autosomal dominant syndrome of hearing loss and hyperkeratosis. The affected family members have high frequency, slowly progressive, bilateral, sensorineural hearing loss and palmoplantar hyperkeratosis. The mutation causes an amino acid substitution (G59A), which may disrupt a reverse turn in the first extracellular loop of connexin 26. Connexin 26 mutations have been reported in syndromes of deafness and palmoplantar keratoderma. These data provide additional evidence for the role of connexin 26 in syndromes of this type. 相似文献
5.
Bazazzadegan N Sheffield AM Sobhani M Kahrizi K Meyer NC Van Camp G Hilgert N Abedini SS Habibi F Daneshi A Nishimura C Avenarius MR Farhadi M Smith RJ Najmabadi H 《American journal of medical genetics. Part A》2011,155(5):1202-1211
Mutations in GJB2, encoding connexin 26 (Cx26), cause both autosomal dominant and autosomal recessive nonsyndromic hearing loss (ARNSHL) at the DFNA3 and DFNB1 loci, respectively. Most of the over 100 described GJB2 mutations cause ARNSHL. Only a minority has been associated with autosomal dominant hearing loss. In this study, we present two families with autosomal dominant nonsyndromic hearing loss caused by a novel mutation in GJB2 (p.Asp46Asn). Both families were ascertained from the same village in northern Iran consistent with a founder effect. This finding implicates the D46N missense mutation in Cx26 as a common cause of deafness in this part of Iran mandating mutation screening of GJB2 for D46N in all persons with hearing loss who originate from this geographic region. 相似文献
6.
Matos TD Caria H Simões-Teixeira H Aasen T Nickel R Jagger DJ O'Neill A Kelsell DP Fialho G 《Journal of medical genetics》2007,44(11):721-725
Mutations in the GJB2 gene are a major cause of non-syndromic recessive hearing loss in many countries. In a significant fraction of patients, only monoallelic GJB2 mutations known to be either recessive or of unclear pathogenicity are identified. This paper reports a novel GJB2 mutation, -3438C-->T, found in the basal promoter of the gene, in trans with V84M, in a patient with profound hearing impairment. This novel mutation can abolish the basal promoter activity of GJB2. These results highlight the importance of extending the mutational screening to regions outside the coding region of GJB2. 相似文献
7.
Soo‐Young Choi Hong‐Joon Park Kyu Yup Lee Emilie Hoang Dinh Qing Chang Shoab Ahmad Sang Heun Lee Jinwoong Bok Xi Lin Un‐Kyung Kim 《Human mutation》2009,30(7):E716-E727
Mutations in the GJB2 gene, which encodes the gap junction (GJ) protein connexin26 (Cx26), are the most common cause of inherited non‐syndromic hearing loss (NSHL). We identified two missense mutations, p.D46E (c.138T>G) and p.T86R (c.257C>G), of GJB2 in Korean HL families. The novel p.D46E mutation exhibited autosomal dominant inheritance, while the p.T86R mutation, which is exclusively found in Asians, segregated with an autosomal recessive pattern. Thus, we sought to elucidate the pathogenic nature of such different inherited patterns of HL. We studied protein localization and gap junction functions in cells transfected with wild‐type or mutant Cx26 tagged with fluorescent proteins, which allowed visual confirmation of homozygous or heterozygous mutant GJs. The Cx26‐D46E mutant was targeted to the plasma membrane, but this mutant protein failed to transfer Ca2+ or propidium iodide intercellularly, suggesting disruption of both ionic and biochemical coupling. Heterozygous GJs also showed dysfunctional intercellular couplings and hemichannel opening, confirming the dominant‐negative nature of the p.D46E mutation. The Cx26‐T86R mutant protein did not form GJs, since the mutated protein was confined in the cytoplasm and not transported to the cell membrane. When Cx26‐T86R was co‐expressed with Cx26‐WT, ionic and biochemical coupling was normal, consistent with the recessive nature of the mutation. These studies revealed distinct pathogenic mechanisms of two GJB2 mutations identified in Korean families. © 2009 Wiley‐Liss, Inc. 相似文献
8.
Tóth T Kupka S Haack B Riemann K Braun S Fazakas F Zenner HP Muszbek L Blin N Pfister M Sziklai I 《Human mutation》2004,23(6):631-632
Mutations in the GJB2 gene encoding the gap-junction protein connexin 26 have been identified in many patients with childhood hearing impairment (HI). One single mutation, c.35delG, accounts for the majority of mutations in Caucasian patients with HI. In the present study we screened 500 healthy control individuals and a group of patients with HI from Northeastern Hungary for GJB2 mutations. The patients' group consisted of 102 familial from 28 families and 92 non-familial cases. The most common mutation in the Hungarian population is the c.35delG, followed by the c.71G>A (p.W24X) mutation. 34.3% of the patients in the familial group were homozygous, and 17.6% heterozygous for 35delG. In the non-familial group the respective values were 37% and 18% (allele frequency: 46.2%). In the general population an allele frequency of 2.4% was determined. Several patients were identified with additional, already described or new GJB2 mutations, mostly in heterozygous state. The mutation c.380G>A (p.R127H) was formerly found only in heterozygous state and its disease relation was controversial. We demonstrated the presence of this mutation in a family with three homozygous patients and 4 heterozygous unaffected family members, a clear indication of recessively inherited HI. Furthermore, we provided evidence for the pathogenic role of two new mutations, c.51C>A (p.S17Y) and c.177G>T (p.G59V), detected in the present study. In the latter case the pattern of inheritance might be dominant. Our results confirm the importance of GJB2 mutations in the Hungarian population displaying mutation frequencies that are comparable with those in the Mediterranean area. 相似文献
9.
Autosomal Dominant Hearing Loss resulting from p.R75Q Mutation in the GJB2 Gene: Nonsyndromic presentation in a South Indian Family
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Amritkumar Pavithra Mathiyalagan Selvakumari Venkatesan Nityaa Narasimhan Sharanya Rajagopalan Ramakrishnan Murali Narasimhan C.R. Srikumari Srisailapathy 《Annals of human genetics》2015,79(1):76-82
Mutations in the GJB2 gene encoding the gap junction protein Connexin 26 have been associated with autosomal recessive as well as dominant nonsyndromic hearing loss. Owing to the involvement of connexins in skin homeostasis, GJB2 mutations have also been associated with syndromic forms of hearing loss showing various skin manifestations. We report an assortatively mating hearing impaired family of south Indian origin with three affected members spread over two generations, having p.R75Q mutation in the GJB2 gene in the heterozygous condition. The inheritance pattern was autosomal dominant with mother and son being affected. Dermatological and histopathologic examinations showed absence of palmoplantar keratoderma. To the best of our knowledge, this is the first report from India on p.R75Q mutation in the GJB2 gene with nonsyndromic hearing loss. 相似文献
10.
目的 检测常染色体隐性遗传耳聋患者GJB2基因突变情况,并分析其与临床表型的关系.方法 收集42例耳聋患者的临床资料,对患者进行纯音电测听检查、声阻抗检测、脑干听觉诱发电位检查;应用聚合酶链反应和直接测序法,对患者和9例患者的父母以及105名正常对照进行GJB2基因检测.结果 两例患者具有235delC纯合性突变,其中1例系感音神经性耳聋,另1例系混合性耳聋;1对混合性耳聋的双生子患者同时携带176de116bp杂合性突变.109G→A、79G→A和341A→G的纯合及杂合突变在患者及正常对照中均有出现.结论 235delC纯合性突变为致病突变,该突变可出现在混合性耳聋中;双生子患者的176de116bp杂合性突变考虑为宫内受到外界环境影响所致,或者由其它基因突变所致.109G→A、79G→A和341A→G考虑为是该基因的多态性,其临床意义仍需进一步探索. 相似文献
11.
Gabriel H Kupsch P Sudendey J Winterhager E Jahnke K Lautermann J 《Human mutation》2001,17(6):521-522
Congenital sensorineural hearing loss affects approximately 1/1,000 live births. Mutations in the gene encoding connexin26 (GJB2) have been described as a major cause of genetic nonsyndromic hearing impairment. Additionally, another gap junction gene, connexin30 (GJB6), was found to be responsible for hereditary hearing loss. We have studied 134 patients with severe to profound hearing loss or deafness and 13 patients with mild to moderate nonsyndromic sensorineural hearing loss in order to evaluate the prevalence of connexin26 and connexin30 mutations in Germany. Mutations in the connexin26 gene were found in 30 patients (22%) with profound to severe hearing impairment whereas only one novel single nucleotide polymorphism (396G-->A) in the connexin30 gene was detected. Among the 13 patients with mild to moderate hearing loss neither mutations in the connexin26 nor in the connexin30 gene could be detected. These results demonstrate that mutations in the connexin26 gene are also a frequent cause of hereditary non-syndromic hearing loss in Germany. Therefore a screening of mutations in the connexin26 gene should be performed in every case of non-syndromic hearing loss of unknown origin. 相似文献
12.
目的 确定一个中国汉族表皮松解性掌跖角化症(epidermolytic palmoplantar keratoderma,EPPK)家系角蛋白9基因(keration 9,KRT9)的突变情况,并分析基因型与表型的对应关系.方法 收集该家系12例患者、13名健康者和100名无亲缘关系的正常人的外周血,提取基因组DNA.采用PCR扩增KRT9基因的第1和第6外显子,对PCR产物进行双向测序以检测基因突变.结果 在所有患者中均检测到KRT9基因第1外显子中的杂合型488G→A突变,导致第163位的精氨酸被谷氨酰胺取代(R163Q).在家系中13名正常人和家系外100名正常人未检测到同样的突变.结论 KRT9基因的错义突变488G→A是该家系发生表皮松解性掌跖角化症的主要原因. 相似文献
13.
14.
Batoul Abi Zamer Mona Mahfood Batoul Saleh Abdullah Fahd Al Mutery Abdelaziz Tlili 《Annals of human genetics》2019,83(6):472-476
Palmoplantar keratoderma (PPK) is a heterogenous group of skin disorders characterized by a persistent thickening of the palms of the hands and sometimes soles of the feet. PPK can be classified into many types, including diffuse, transgradient, and focal or striate, where the areas of palmoplantar skin are alternatively thickened. Mutations in four main genes, keratin 9 (KRT9), keratin 1 (KRT1), desmoglein (DSG1), and desmoplakin (DSP), have been associated with PPK. Striate PPK (SPPK) is commonly caused by mutations in DSG1. However, DSP and KRT1 gene mutations have been identified in some cases. In this study, fragment and sequencing analysis were performed for a large Syrian family with dominant SPPK. Segregation analysis showed a linkage with DSG1 gene. Direct Sanger sequencing identified a new mutation c.dup165_168AGCA. This frameshift mutation was heterozygous in all affected family members and absent in all normal individuals. 相似文献
15.
16.
Primignani P Castorina P Sironi F Curcio C Ambrosetti U Coviello DA 《Clinical genetics》2003,63(6):516-521
Mutations of the GJB2 gene, encoding Connexin 26, are the most common cause of hereditary congenital hearing loss in many countries, and account for up to 50% of cases of autosomal-recessive non-syndromic deafness. By contrast, only a few GJB2 mutations have been reported to cause an autosomal-dominant form of non-syndromic deafness. We report on a family from southern Italy in whom dominant, non-syndromic, post-lingual hearing loss is associated with a novel missense mutation in the GJB2 gene. Direct sequencing of the gene showed a heterozygous G-->A transition at nucleotide 535, resulting in an aspartic acid to asparagine amino acid substitution at codon 179 (D179N). This mutation occurred in the second extracellular domain (EC2), which would seem to be very important for connexon-connexon interaction. 相似文献
17.
18.
目的 对6个遗传性非综合征型耳聋家系成员的GJB2基因编码序列进行分析,寻找耳聋患者的致病基因突变,探讨GJB2基因突变致病的遗传模式.方法 提取患者及家系成员的外周血基因组DNA,扩增GJB2基因的编码序列,然后对扩增产物进行DNA测序,对出现重叠峰形的扩增产物进行TA克隆后再测序,确定基因突变是否存在于同一拷贝.结果 6个遗传性非综合征型耳聋家系中,4个家系是GJB2基因突变所致.患者的GJB2基因突变包括235delC、299-300delAT、79G→A+341A→G和109G→A.非致聋突变79G→A与341A→G组合具有致聋效应,109G→A和235delC的杂合突变可能也有致聋效应.结论 GJB2基因突变致聋具有明显异质性,非致聋突变并非完全不致聋,环境因素或其它基因可能参与GJB2基因突变所致耳聋. 相似文献
19.
The frequency of GJB2 and GJB6 mutations in the New York State newborn population: feasibility of genetic screening for hearing defects 总被引:3,自引:0,他引:3
Fitzgerald T Duva S Ostrer H Pass K Oddoux C Ruben R Caggana M 《Clinical genetics》2004,65(4):338-342
In the US, approximately one in every 1000 children has hearing loss sufficiently severe to interfere with the acquisition of normal speech [Ann NY Acad Sci 630 (1991) 16]. The causes of non-syndromic hearing loss (NSHL) are known to be heterogeneous, with genetic factors accounting for 50-75%[Am J Med Genet 46 (1993) 486]. Often individuals with NSHL thought to be caused by mutations in GJB2 have only one detectable mutant allele [Am J Hum Genet 62 (1998) 792, Hum Mol Genet 6 (12) (1997) 2173]. Another gene that has been identified as a possible cause of NSHL is GJB6 that codes for the gap junction protein, connexin 30. A consecutive series of anonymous newborn dried blood specimens (n = 2089) was tested for two GJB2 mutations: (i) 35delG, a pan-ethnic mutation; and (ii) 167delT, a mutation more frequently found in individuals of Ashkenazi Jewish and Mediterranean descents. Mutation detection was validated using allele-specific oligonucleotide hybridization in single wells. Once the positive samples had been identified, the samples were pooled and retested. All positives in the individual experiment were correctly identified in the pooled experiment. The same random set of anonymous newborn dried blood specimens plus some additional samples were tested (n = 2112) for the 342-kb deletion in the GJB6 gene. 相似文献
20.
Gasmelseed NM Schmidt M Magzoub MM Macharia M Elmustafa OM Ototo B Winkler E Ruge G Horstmann RD Meyer CG 《Human mutation》2004,23(2):206-207
A large proportion of non-syndromic autosomal recessive deafness (NSARD) in many populations is caused by variants of the GJB2 gene. Here, the frequency of GJB2 variants was studied in 406 and 183 apparently unrelated children from Kenya and Sudan, respectively, with mostly severe to profound non-syndromic deafness. Nine (2.2 %) Kenyan and 12 (6.6 %) of the Sudanese children only were carriers of variants within the coding sequence of the GJB2 gene. Variants in the 5'-adjacent region were detected in further 115 individuals. A total of 10 novel variants was recognized, among them four variants in the adjacent 5'-region of the GJB2 coding exon 2 (g.3318-6T>A, g.3318-15C>T, g.3318-34C>T, g.3318-35T>G), a 6 base-pair deletion (g.3455_3460del [p.Asp46_Gln48delinsGlu]), a variant leading to a stop codon (g.3512C>A [p.Tyr65X]), synonymous variants (g.3395C>T [p.Thr26], g.3503C>T [p.Asn62], g.3627A>C [p.Arg104]), and one non-synonymous variant (g.3816C>A [p.Val167Met]). In addition, the previously described variants g.3352delG (commonly designated 30delG or 35 delG), g.3426G>A [p.Val37Ile], g.3697G>A [p.Arg127His], g.3774G>A [p.Val153Ile], and g.3795G>A [p.Gly160Ser] were identified. With the exception of g.3318-34C>T and g.3352delG, all variants occurred heterozygously. For most of the variants identified in the Kenyan and Sudanese study population, a causative association with NSARD appears to be unlikely. Compared to many other ethnic groups, deafness-associated variants of the coding region of GJB2 are rare in Sudan and Kenya, suggesting a role of other genetic, or epigenetic factors as a cause for deafness in these countries. 相似文献