A Mayan founder mutation is a common cause of deafness in Guatemala

Over 5% of the world's population has varying degrees of hearing loss. Mutations in GJB2 are the most common cause of autosomal recessive non‐syndromic hearing loss (ARNHL) in many populations. The frequency and type of mutations are influenced by ethnicity. Guatemala is a multi‐ethnic country with four major populations: Maya, Ladino, Xinca, and Garifuna. To determine the mutation profile of GJB2 in a ARNHL population from Guatemala, we sequenced both exons of GJB2 in 133 unrelated families. A total of six pathogenic variants were detected. The most frequent pathogenic variant is c.131G>A (p.Trp44*) detected in 21 of 266 alleles. We show that c.131G>A is associated with a conserved haplotype in Guatemala suggesting a single founder. The majority of Mayan population lives in the west region of the country from where all c.131G>A carriers originated. Further analysis of genome‐wide variation of individuals carrying the c.131G>A mutation compared with those of Native American, European, and African populations shows a close match with the Mayan population.     

Identities, frequencies and origins of TMC1 mutations causing DFNB7/B11 deafness in Pakistan

Non-syndromic deafness is genetically heterogeneous. We previously reported that mutations of transmembrane channel-like gene 1 (TMC1) cause non-syndromic recessive deafness at the DFNB7/B11 locus on chromosome 9q13-q21 in nine Pakistani families. The goal of this study was to define the identities, origins and frequencies of TMC1 mutations in an expanded cohort of 557 large Pakistani families segregating recessive deafness. We screened affected family members for homozygosity at short-tandem repeats flanking known autosomal recessive (DFNB) deafness loci, followed by TMC1 sequence analysis in families segregating deafness linked to DFNB7/B11. We identified 10 new families segregating DFNB7/B11 deafness and TMC1 mutations, including three novel alleles. Overall, 9 different TMC1 mutations account for deafness in 19 (3.4%) of the 557 Pakistani families. A single mutation, p.R34X, causes deafness in 10 (1.8%) of the families. Genotype analysis of p.R34X-linked markers indicates that it arose from a common founder. We also detected p.R34X among normal control samples of African-American and northern European origins, raising the possibility that p.R34X and other mutations of TMC1 are prevalent contributors to the genetic load of deafness across a variety of populations and continents.     

汉族儿童MBL基因启动子-221位点、外显子I区SNP和基因单体型分析

研究浙江省汉族儿童MBL基因启动子-221位点和外显子I区单核苷酸多态性(SNP)、基因单体型与血浆MBL水平的关系。血浆MBL浓度的检测采用ELISA法,MBL基因SNP分析采用序列分析法,基因单体型分析采用SHEsis软件,统计分析采用SPSS软件11.0版。结果105例汉族儿童中MBL基因启动子区-221位点X/Y和Y/Y基因型分别占19%和81%,该位点变异频率为0.095;外显子I基因型A/A、A/B和B/B分别占69.5%、27.6%和2.9%,B型变异频率为0.167。基因单体型有YA、YB、XA三种,其中以YA最多见,频率为0.741,其次是YB,频率为0.164。血浆MBL浓度范围为3~6 025 ng/ml,中位数为1057 ng/ml,外显子A/A型的MBL浓度显著高于A/B型,后者又显著高于B/B型;而启动子Y/Y型的MBL浓度比X/Y型高。本研究中汉族儿童MBL基因外显子I区+230位点的变异频率为0.167,外显子I区+230位点变异可导致血浆MBL水平明显下降。     

The contribution of USH1C mutations to syndromic and non-syndromic deafness in the UK

Denaturing high-performance liquid chromatography (DHPLC) was used to screen 14 UK patients with Usher syndrome type 1, in order to assess the contribution of mutations in USH1C to type 1 Usher. In addition, 16 Caucasian sib pairs and two small consanguineous families with non-syndromic deafness, who were concordant for haplotypes around DFNB18, were also screened for mutations in the USH1C gene. Two Usher type 1 patients were found to have the 238-239insC mutation reported previously; one of Greek Cypriot origin was homozygous for the mutation and another Caucasian was heterozygous. This indicates that mutations in the USH1C gene make a greater contribution to Usher syndrome type 1 than originally thought, which has implications for the genetic testing of families with Usher syndrome in the UK. Analysis using intragenic single nucleotide polymorphisms (SNPs) revealed that the haplotypic background bearing this common mutation was not consistent across the gene in two families, and that there are either two haplotypes on which the mutation has arisen or that there has been a recombination on a single haplotype. We found no evidence of mutations in USH1C in the patients with non-syndromic deafness, suggesting that the gene is not a major contributor to autosomal-recessive non-syndromic deafness in the UK.     

Association of Interleukin‐1 beta and tumor necrosis factor‐alpha genetic polymorphisms with gastric cancer in India

Interleukin 1 beta (IL‐1β) and Tumor necrosis factor alpha (TNF‐α) are key inflammatory cytokines whose polymorphisms have been correlated with increased susceptibility to gastric cancer (GC). Since geographical and racial differences exist in cancer rates, our study was aimed to evaluate the first possible association of polymorphisms in these genes with GC risk in West Bengal, India. Polymorphisms in IL‐1β and TNF‐α genes were genotyped in 120 GC patients and 135 healthy individuals. Combined effect of the SNPs in both genes with GC risk was determined through allele dosage analysis (ADA) and the survival data were analyzed by Log Rank Test. The study results revealed that IL‐1β rs1143627: T > C, rs16944: C > T (p = 0.001;OR = 1.85; 95% CI 1.30‐2.63) and rs1143633: G > A (p < 0.0001; OR = 2.53; 95% CI 1.67‐3.83) and TNF‐α rs1800630: C > A, rs1799964: T > C (p < 0.0001; OR = 2.31; 95% CI 1.54‐3.46) polymorphisms significantly contributed toward GC risk. Moreover, ADA showed that carriage of 7 “effective” risk alleles conferred a risk of almost 10‐fold in comparison to individuals carrying less than 3 “effective” risk alleles. Our survival analysis also indicated a significant association between IL‐1β rs1143627: T > C and rs16944: C > T and patient survivability. The presence of H. pylori enhanced the risk in individuals with IL‐1β rs1143627:CC and rs16944:TT genotypes. Further, meta‐analysis revealed significant association of IL‐1β rs1143627: T > C (p = 0.026; OR = 4.165; 95% CI 1.18‐14.65) and rs16944: C > T (p = 0.01; OR = 5.49; 95% CI 1.48‐20.37) in presence of H. pylori with gastric cancer in Asian population though no significant difference (p > 0.05) was found when compared to absence of H. pylori Environ. Mol. Mutagen. 59:653–667, 2018. © 2018 Wiley Periodicals, Inc.     

Novel glucokinase mutations in patients with monogenic diabetes - clinical outline of GCK-MD and potential for founder effect in Slavic population

Glucokinase (GCK) gene mutations are the causative factor of GCK-MD (monogenic diabetes) characterized by a mild clinical phenotype and potential for insulin withdrawal. This study presents the results of a nationwide genetic screening for GCK-MD performed in Poland. A group of 194 patients with clinical suspicion of GCK-MD and 17 patients with neonatal diabetes were subjected to GCK sequencing. Patients negative for GCK mutations were subjected to multiplex ligation-dependent probe amplification (MLPA) to detect deletions or insertions. A total of 44 GCK heterozygous mutations were found in 68 probands (35%). Among those, 20 mutations were novel ones: A282fs, D198V, E158X, G246V, G249R, I348N, L165V, L315Q, M115I, N254S, P284fs, Q338P, R377L, R43C, R46S, S212fs, S212P, T255N, V406A and Y214D. No abnormalities were detected in MLPA analysis. Homozygous D278E mutation was found in one patient with neonatal diabetes. The most frequently observed combinations of symptoms typical for GCK-MD were mild diabetes and/or fasting hyperglycaemia (98.3%), positive C-peptide at diagnosis (76%) and dominant mode of inheritance (59%). This study outlines numerous novel mutations of the GCK gene present in white Caucasians of Slavic origin. Thorough clinical assessment of known factors associated with GCK-MD may facilitate patient selection.     

Novel genetic polymorphisms in DNA repair genes: O6‐methylguanine‐DNA methyltransferase (MGMT) and N‐methylpurine‐DNA glycosylase (MPG) in lung cancer patients from Poland

Individuals with a decreased DNA repair capacity are at increased cancer risk. The aim of our investigation was to detect genetic polymorphisms in DNA repair genes. Two genes, MPG and MGMT, involved in repair of alkylated purines, have been selected. The genetic polymorphisms in the coding exons 2, 3 and 4 of MPG and in the enhancer region of MGMT were searched for in DNA samples from a group of 33 non‐small‐cell lung cancer (NSCLC) patients from Poland. The PCR products were sequenced with fluorescently labeled terminators and separated on automatic sequencer. Two polymorphisms in MPG were found: in exon 2: CGC→TGC, (8603C>T, Genbank Accession Z69720) and in exon 3: CCG→CCA, (12235G>A, Genbank Accession Z69720). The polymorphism in exon 2 results in amino acid substitution (Arg>Cys). Three polymorphisms within or around 59 bp enhancer of MGMT were detected: 1) 1034A>G (Genbank Accession X61657), 2) 1099C>T (Genbank Accession X61657), 3) 79G>T (Genbank Accession U95038). Polymorphism 2 is located in the 59‐bp enhancer sequence, within a palindrome GGTGCGCACC. Polymorphism 3 destroys an inverted repeat GGGTGGGGGGCCGCCCTGACCCCCACCC that contains two PuF binding sequences GGGTGGG separated by Sp1 site. The nature and location of these polymorphisms is consistent with the hypothesis that they may have functional significance. Hum Mutat 14:269‐270, 1999. © 1999 Wiley‐Liss, Inc.     

Novel recessive PDZD7 biallelic mutations in two Chinese families with non‐syndromic hearing loss

Autosomal recessive non‐syndromic hearing loss (ARNSHL) is a highly heterogeneous genetic condition. PDZD7 has emerged as a new genetic etiology of ARNSHL. Biallelic mutations in the PDZD7 gene have been reported in two German families, four Iranian families, and a Pakistani family with ARNSHL. The effect of PDZD7 on ARNSHL in other population has yet to be elucidated. Two Chinese ARNSHL families, each of which had two affected siblings, were included in this study. The families underwent target region capture and high‐throughput sequencing to analyze the exonic, splice‐site, and intronic sequences of 128 genes. Furthermore, 1751 normal Chinese individuals served as controls, and 122 Chinese families segregating with apparent ARNSHL, who had been previously excluded for variants in the common deafness genes GJB2 and SLC26A4, were subjected to screening for candidate mutations. We identified a novel homozygous missense mutation (p.Arg66Leu) and novel compound heterozygous frameshift mutations (p.Arg56fsTer24 and p.His403fsTer36) in Chinese families with ARNSHL. This is the first report to identify PDZD7 as an ARNSHL‐associated gene in the Chinese population. Our finding could expand the pathogenic spectrum and strengthens the clinical diagnostic role of the PDZD7 gene in ARNSHL patients.     

西北地区汉族人群FCAMR基因单核苷酸多态性及单体型分析

为研究西北地区汉族人群IgAIg MFc高亲和力受体(Fc receptor IgAIg Mhigh affinity,FCAMR/Fcα/μR)基因单核苷酸多态性(SNP)及单体型的频率。我们采用聚合酶链反应后直接测序方法,对西北地区79(男45,女34)名没有亲缘关系的汉族健康个体FCAMR基因,T549C(rs1856746),A457G(rs3813952),G421A(rs1340232)和A298G(rs3813950)4个SNP位点进行基因分型。用SHEsis软件分析FCAMR基因的单体型频率。本研究发现西北地区汉族人群中T549C(rs1856746)位点,等位基因频率C是38.6%,T是61.4%;A457G(rs3813952)位点,等位基因频率G是5.7%,A是94.3%;G421A(rs1340232)位点,等位基因频率A是17.1%,G是82.9%,A298G(rs3813950)位点,等位基因频率G是4.4%,A是95.6%。西北地区汉族人群中FCAMR基因T549C(rs1856746)、A457G(rs3813952)、G421A(rs1340232)和A298G(rs3813950)4个位点构成的3种主要单体型率(频率>10%)T/A/G/A是60.5%,C/A/A/A是17.1%和C/A/G/A是16.7%。本研究分析了西北地区汉族人群FCAMR基因T549C(rs1856746)、A457G(rs3813952)、G421A(rs1340232)和A298G(rs3813950)4个SNP位点的基因型频率、等位基因频率和单体型频率,为研究该地区FCAMR基因单核苷酸多态性与免疫反应以及相关疾病如IgA肾病易感性之间的相关性提供研究基础。     

A c.3216_3217delGA mutation in AGL gene in Tunisian patients with a glycogen storage disease type III: evidence of a founder effect

Mili A, Ben Charfeddine I, Amara A, MamaÏ O, Adala L, Ben Lazereg T, Bougulia J, Saad A, Limem K, Gribaa M. A c.3216_3217delGA mutation in AGL gene in Tunisian patients with a glycogen storage disease type III: evidence of a founder effect. Glycogen storage disease type III (GSD III) is an autosomal recessive disorder characterized by excessive accumulation of abnormal glycogen in the liver and muscles and caused by deficiency in the glycogen debranching enzyme, the amylo‐1,6‐glucosidase (AGL). In this study, we report the clinical, biochemical and genotyping features of five unrelated GSD III patients coming from the same region in Tunisia. The concentration of erythrocyte glycogen and AGL activity were measured by colorimetric and fluorimetric methods, respectively. Four CA/TG microsatellite markers flanking the AGL gene in chromosome 1 were amplified with fluoresceinated primers. The full coding exons and their relevant exon–intron boundaries of the AGL gene were directly sequenced for the patients and their parents. All patients showed a striking increase of erythrocytes glycogen content. No AGL activity was detected in peripheral leukocytes. Sequencing of the AGL gene identified a c.3216_3217delGA (p.Glu1072AspfsX36) mutation in the five patients which leads to a premature termination, abolishing the AGL activity. Haplotype analysis showed that the mutation was associated with a common homozygote haplotype. Our results suggested the existence of a founder effect responsible for GSD III in this region of Tunisia.     

Mutation analysis of TMC1 identifies four new mutations and suggests an additional deafness gene at loci DFNA36 and DFNB7/11

Hearing loss is the most frequent sensorineural disorder affecting 1 in 1000 newborns. In more than half of these babies, the hearing loss is inherited. Hereditary hearing loss is a very heterogeneous trait with about 100 gene localizations and 44 gene identifications for non-syndromic hearing loss. Transmembrane channel-like gene 1 ( TMC1 ) has been identified as the disease-causing gene for autosomal dominant and autosomal recessive non-syndromic hearing loss at the DFNA36 and DFNB7/11 loci, respectively. To date, 2 dominant and 18 recessive TMC1 mutations have been reported as the cause of hearing loss in 34 families. In this report, we describe linkage to DFNA36 and DFNB7/11 in 1 family with dominant and 10 families with recessive non-syndromic sensorineural hearing loss. In addition, mutation analysis of TMC1 was performed in 51 familial Turkish patients with autosomal recessive hearing loss. TMC1 mutations were identified in seven of the families segregating recessive hearing loss. The pathogenic variants we found included two known mutations, c.100C>T and c.1165C>T, and four new mutations, c.2350C>T, c.776+1G>A, c.767delT and c.1166G>A. The absence of TMC1 mutations in the remaining six linked families implies the presence of mutations outside the coding region of this gene or alternatively at least one additional deafness-causing gene in this region. The analysis of copy number variations in TMC1 as well as DNA sequencing of 15 additional candidate genes did not reveal any proven pathogenic changes, leaving both hypotheses open.     

Single‐nucleotide polymorphisms associated with pemphigus vulgaris: Potent markers for better treatment and personalized medicine

Pemphigus vulgaris (PV) is a rare autoimmune blistering disorder, which could affect both skin and mucosal surfaces. There is increasing evidence that genetics plays a critical role in PV development, severity and prognosis. Single‐nucleotide polymorphisms (SNPs) are the most common type of genetic variation among people and have been widely evaluated in most diseases. However, there are few studies regarding the roles of SNPs in the PV. Here, we reviewed both pathogenic and protective roles of the SNPs in non‐HLA genes regarding the PV. Among the large number of studied SNPs, it was found that several SNPs in different genes might control the susceptibility of PV, including TNFA (rs361525, rs1800629, rs1800629), IL10 (rs1800871, rs1800896, rs1800871, and rs1800872), IL6 (rs1800795), CTLA4 (rs231775), ICOS (rs10932029), CD86 (rs1129055), DSG3 (rs8085532, rs3911655, rs3848485, rs3794925, rs1466379), ST18 (rs2304365, rs17315309) and TAP2 (rs7454108), probably in a population‐specific manner. Moreover, SNPs in glucocorticoid receptor, also known as nuclear receptor subfamily 3 group C member 1 (NR3C1) gene, including rs11745958, rs17209237, rs33388, rs7701443 as well as rs116855232 at NUDT15, seem to be associated with therapeutic outcomes in PV patients. Additionally, variations in the other genes involved in the drugs' metabolisms, pharmacokinetics and pharmacodynamics such as rs396991 in FCGR3A gene could be used for the prediction of clinical response to drugs and side effects. Taken together, SNPs seem to be valuable tools for better management of PV patients. Further studies need to be conducted to evaluate SNPs in genes that control immune responses and apoptosis.     

Novel missense mutations of TMPRSS3 in two consanguineous Tunisian families with non‐syndromic autosomal recessive deafness

Recently the TMPRSS3 gene, which encodes a transmembrane serine protease, was found to be responsible for two non‐syndromic recessive deafness loci located on human chromosome 21q22.3, DFNB8 and DFNB10. We found evidence for linkage to the DFNB8/10 locus in two unrelated consanguineous Tunisian families segregating congenital autosomal recessive sensorineural deafness. The audiometric tests showed a loss of hearing greater than 70 dB, in all affected individuals of both families. Mutation screening of TMPRSS3 revealed two novel missense mutations, W251C and P404L, altering highly conserved amino acids of the serine protease domain. Both mutations were not found in 200 control Tunisian chromosomes. The detection of naturally‐occurring TMPRSS3 missense mutations in deafness families identifies functionally important amino acids. Comparative protein modeling of the TMPRSS3 protease domain predicted that W251C might lead to a structural rearrangement affecting the active site H257 and that P404L might alter the geometry of the active site loop and therefore affect the serine protease activity. Hum Mutat 18:101–108, 2001. © 2001 Wiley‐Liss, Inc.     

湖北汉族变应性哮喘患者GPR154基因单倍型分析

目的探讨G蛋白偶联受体154(Gprotein-coupled receptor154,GPR154)基因多态性与湖北汉族变应性哮喘易感性间的关系。方法用聚合酶链反应和限制性片段长度多态性对145例变应性哮喘患者和120名健康人群GPR154基因的SNP563704和SNP522363位点的多态性进行分析。结果(1)变应性哮喘患者SNP563704 CC、CT和TT基因型频率是0.324、0.524和0.152;与对照组相比差异无统计学意义(χ2=1·880,P>0.05);变应性哮喘组不同基因型间血清总IgE水平差异无统计学意义(F=0.714,P>0.05)。(2)变应性哮喘患者SNP522363CC、CG和GG基因型频率是0.289、0.521和0.190;与对照组相比差异无统计学意义(χ2=0.700,P>0.05);变应性哮喘组不同基因型间血清总IgE水平差异无统计学意义(F=0·083,P>0.05)。(3)对SNP522363和SNP563704进行单倍型分析,4种频率大于0.03的单倍型在哮喘组和对照组间差异有统计学意义(χ2=16.50,P<0.01)。哮喘组CT和GT单倍型频率显著高于对照组,差异有统计学意义(P=0.015;P=0.002)。结论湖北汉族变应性哮喘易感性与单个的单核甘酸多态性无关,但与SNP522363和SNP563704组成的单倍型显著相关。     

Novel missense mutations of TMPRSS3 in two consanguineous Tunisian families with non‐syndromic autosomal recessive deafness

Regarding this article: The corresponding author of this article regrets that the last name of one of the co‐authors was misspelled. Dr. M’hamed GRATI was incorrectly listed as “GRATRI” in the author list. Since it is too late for the publisher to correct this error in the actual journal article, we wish to clarify the matter for the record, for indexing and abstracting purposes.     

Functional characterization of the first missense variant in CEP78, a founder allele associated with cone‐rod dystrophy,hearing loss,and reduced male fertility

Inactivating variants in the centrosomal CEP78 gene have been found in cone‐rod dystrophy with hearing loss (CRDHL), a particular phenotype distinct from Usher syndrome. Here, we identified and functionally characterized the first CEP78 missense variant c.449T>C, p.(Leu150Ser) in three CRDHL families. The variant was found in a biallelic state in two Belgian families and in a compound heterozygous state—in trans with c.1462‐1G>T—in a third German family. Haplotype reconstruction showed a founder effect. Homology modeling revealed a detrimental effect of p.(Leu150Ser) on protein stability, which was corroborated in patients' fibroblasts. Elongated primary cilia without clear ultrastructural abnormalities in sperm or nasal brushes suggest impaired cilia assembly. Two affected males from different families displayed sperm abnormalities causing infertility. One of these is a heterozygous carrier of a complex allele in SPAG17, a ciliary gene previously associated with autosomal recessive male infertility. Taken together, our data indicate that a missense founder allele in CEP78 underlies the same sensorineural CRDHL phenotype previously associated with inactivating variants. Interestingly, the CEP78 phenotype has been possibly expanded with male infertility. Finally, CEP78 loss‐of‐function variants may have an underestimated role in misdiagnosed Usher syndrome, with or without sperm abnormalities.     

A Dominant Mutation in the Stereocilia‐Expressing Gene TBC1D24 is a Probable Cause for Nonsyndromic Hearing Impairment

Mutations in TBC1D24 have been linked to a variety of epileptic syndromes and recently to syndromic hearing impairment DOORS syndrome and nonsyndromic hearing impairment DFNB86. All TBC1D24 mutations reported so far were inherited in the recessive mode. In a dominant family segregated with late‐onset, progressive, nonsyndromic hearing impairment, linkage analysis revealed a 2.07 Mb candidate region on chromosome 16p13.3 that contains TBC1D24. Whole‐exome sequencing identified a heterozygous p.Ser178Leu variant of TBC1D24 as the only candidate mutation segregating with the hearing loss within the family. In perinatal mouse cochlea, we detected a restricted expression of Tbc1d24 in the stereocilia of the hair cells as well as in the spiral ganglion neurons. Our study suggested that the p.Ser178Leu mutation of TBC1D24 is a probable cause for dominant, nonsyndromic hearing impairment. Identification of TBC1D24 as the stereocilia‐expressing gene may shed new light on its specific function in the inner ear.     

Different functional consequences of two missense mutations in the GJB2 gene associated with non‐syndromic hearing loss

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.