Maternally inherited hearing loss is associated with the novel mitochondrial tRNASer(UCN) 7505T>C mutation in a Han Chinese family

Abstract Variations in mitochondrial genome have been found to be associated with hearing loss. Of these, the mitochondrial 12S rRNA and tRNASer(UCN) are the hot-spots for pathogenic variants associated with deafness. To understand the putative role of mitochondrial DNA (mtDNA) variants in hearing loss, we recently screened the variants in mitochondrial genomes in patients with deafness from the Hangzhou area of Zhejiang Province, People’s Republic of China (PRC). In this study, we describe a maternally-inherited Han Chinese family with high penetrance of hearing loss, notably, the penetrance of hearing loss in this family were 80.0 and 40.0%, when the aminoglycoside was included or excluded. Three matrilineal relatives in this pedigree exhibited different levels of hearing loss with different age at onset. In addition, sequence analysis of the complete mitochondrial genome showed the presence of the well-known C1494T pathogenic variant in the 12S rRNA gene and the G7444A pathogenic variant in the COI/ tRNASer(UCN). The C1494T anomaly had been reported to be a pathogenic mutation associated with aminoglycoside-induced and nonsyndromic hearing loss (AINHL), while the G7444A was considered as a secondary mutation associated with deafness. However, the lack of functional variants in GJB2 and TRMU genes suggested that nuclear modified genes may not play important roles in deafness expression. Thus, the combination of G7444A and C1494T pathogenic variants in the mitochondrial genome may account for the high penetrance of hearing loss in this Chinese family.

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MITF p.Arg217Thr Variant Identified in a Han Chinese Family with Tietz/Waardenburg Syndrome

BioMed Research International ◽

10.1155/2021/4381272 ◽

2021 ◽

Vol 2021 ◽

pp. 1-6

Author(s):

Rong Yu ◽

Lv Liu ◽

Ya-Li Li ◽

Liang-Liang Fan

Keyword(s):

Hearing Loss ◽

Genetic Disorders ◽

Molecular Genetic ◽

Genetic Diagnosis ◽

Han Chinese ◽

White Hair ◽

Chinese Family ◽

Waardenburg Syndrome ◽

Genetic Lesion

Waardenburg syndrome (WS) is a group of rare genetic disorders characterized by hearing loss, changes in coloring of hair, skin, and eyes, and alterations in the shape of the face. Tietz syndrome is another rare disorder which presented similar phenotypes to WS. Patients with Tietz/Waardenburg syndrome often present with pale blue eyes, albino skin, and distinctive hair coloring, such as a patch of white hair or hair that prematurely turns gray. At present, more than six candidate genes are responsible for four types of Waardenburg syndrome and Tietz syndrome. This study is aimed at identifying the pathogenic gene variants in a three-generation Han Chinese family with hearing loss, blue-gray iris, albino skin, and white hair. In order to discover the molecular genetic lesion underlying the disease phenotype, whole exome sequencing in the proband, with Tietz/Waardenburg syndrome phenotypes, of a Han Chinese family from HeBei, China, was conducted. A novel heterozygous c.650G>C/p.Arg217Thr variant in melanocyte inducing transcription factor (MITF) was identified. Sanger sequencing further validated that this mutation existed in three affected individuals and absent in healthy family members. Bioinformatics analysis predicted that this mutation was deleterious. Our study further identified the genetic lesion of the family. Simultaneously, our study may also contribute to genetic counseling, embryonic screening of in vitro fertilized embryos, and prenatal genetic diagnosis of patients with Tietz/Waardenburg syndrome, especially for the proband, unmarried and unpregnant women, to reduce familial transmission in this Han Chinese family.

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A COL4A5 Missense Variant in a Han-Chinese Family with X-linked Alport Syndrome

Current Molecular Medicine ◽

10.2174/1566524019666190906144214 ◽

2019 ◽

Vol 19 (10) ◽

pp. 758-765

Author(s):

Yuan Wu ◽

Yi Guo ◽

Jinzhong Yuan ◽

Hongbo Xu ◽

Yong Chen ◽

...

Keyword(s):

Hearing Loss ◽

Sanger Sequencing ◽

Alport Syndrome ◽

Genetic Defect ◽

Missense Variant ◽

Han Chinese ◽

Chinese Family ◽

Chain Gene ◽

Renal Disorder ◽

The Family

Background: Alport syndrome (AS) is an inherited familial nephropathy, characterized by progressive hematuric nephritis, bilateral sensorineural hypoacusis and ocular abnormalities. X-linked AS (XLAS) is the major AS form and is clinically heterogeneous, and it is associated with defects in the collagen type IV alpha 5 chain gene (COL4A5). Objective: The purpose of this research is to detect the genetic defect responsible for renal disorder in a 3-generation Han-Chinese pedigree. Methods: Detailed family history and clinical data of the family members were collected and recorded. Whole exome sequencing (WES) was applied in the proband to screen potential genetic variants, and then Sanger sequencing was used to verify the variant within the family. Two hundred unrelated ethnically matched normal individuals (male/female: 100/100, age 37.5 ± 5.5 years) without renal disorder were recruited as controls. Results: Three patients (I:1, II:1 and II:2) presented microscopic hematuria and proteinuria, and the patient I:1 developed uremia and end stage renal disease (ESRD) by age 55 and showed sensorineural hearing loss. Patient II:2 developed mild left ear hearing loss. Cataracts were present in patients I:1 and II:1. A COL4A5 gene missense variant, c.2156G>A (p.G719E), located in the Gly-X-Y repeats of exon 28, was identified to co-segregate with the renal disorder in this family. The variant was absent in 200 ethnically matched controls. Conclusion: By conducting WES and Sanger sequencing, a COL4A5 missense variant, c.2156G>A (p.G719E), was identified to co-segregate with the renal disorder, and it is possible that this variant is the genetic cause of the disorder in this family. Our study may extend the mutation spectrum of XLAS and may be useful for genetic counseling of this family. Further functional studies associated with genetic deficiency are warranted in the following research.

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Failures in Mitochondrial tRNA Met and tRNA Gln Metabolism Caused by the Novel 4401A>G Mutation Are Involved in Essential Hypertension in a Han Chinese Family

Hypertension ◽

10.1161/hypertensionaha.109.129270 ◽

2009 ◽

Vol 54 (2) ◽

pp. 329-337 ◽

Cited By ~ 48

Author(s):

Ronghua Li ◽

Yuqi Liu ◽

Zongbin Li ◽

Li Yang ◽

Shiwen Wang ◽

...

Keyword(s):

Essential Hypertension ◽

Han Chinese ◽

Chinese Family ◽

The Novel ◽

Mitochondrial Trna

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Maternally Inherited Essential Hypertension Is Associated With the Novel 4263A>G Mutation in the Mitochondrial tRNA Ile Gene in a Large Han Chinese Family

Circulation Research ◽

10.1161/circresaha.110.231811 ◽

2011 ◽

Vol 108 (7) ◽

pp. 862-870 ◽

Cited By ~ 81

Author(s):

Shiwen Wang ◽

Ronghua Li ◽

Andrea Fettermann ◽

Zongbin Li ◽

Yaping Qian ◽

...

Keyword(s):

Essential Hypertension ◽

Han Chinese ◽

Chinese Family ◽

The Novel ◽

Mitochondrial Trna

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Hearing loss and epilepsy may be associated with the novel mito-chondrial TrnaSer(UCN) 7472delC mutation in a Chinese family

Hereditas (Beijing) ◽

10.3724/sp.j.1005.2008.01557 ◽

2009 ◽

Vol 30 (12) ◽

pp. 1557-1562 ◽

Cited By ~ 2

Author(s):

Jian-Yue ZHAO

Keyword(s):

Hearing Loss ◽

Chinese Family ◽

The Novel

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A Novel Truncating Mutation in HOMER2 Causes Nonsyndromic Progressive DFNA68 Hearing Loss in a Spanish Family

Genes ◽

10.3390/genes12030411 ◽

2021 ◽

Vol 12 (3) ◽

pp. 411

Author(s):

María Lachgar ◽

Matías Morín ◽

Manuela Villamar ◽

Ignacio del Castillo ◽

Miguel Ángel Moreno-Pelayo

Keyword(s):

Hearing Loss ◽

Stop Codon ◽

Coiled Coil ◽

Premature Stop Codon ◽

Scaffolding Protein ◽

Common Mechanism ◽

Chinese Family ◽

Truncating Mutation ◽

Spanish Family ◽

Sensory Defect

Nonsyndromic hereditary hearing loss is a common sensory defect in humans that is clinically and genetically highly heterogeneous. So far, 122 genes have been associated with this disorder and 50 of them have been linked to autosomal dominant (DFNA) forms like DFNA68, a rare subtype of hearing impairment caused by disruption of a stereociliary scaffolding protein (HOMER2) that is essential for normal hearing in humans and mice. In this study, we report a novel HOMER2 variant (c.832_836delCCTCA) identified in a Spanish family by using a custom NGS targeted gene panel (OTO-NGS-v2). This frameshift mutation produces a premature stop codon that may lead in the absence of NMD to a shorter variant (p.Pro278Alafs*10) that truncates HOMER2 at the CDC42 binding domain (CBD) of the coiled-coil structure, a region that is essential for protein multimerization and HOMER2-CDC42 interaction. c.832_836delCCTCA mutation is placed close to the previously identified c.840_840dup mutation found in a Chinese family that truncates the protein (p.Met281Hisfs*9) at the CBD. Functional assessment of the Chinese mutant revealed decreased protein stability, reduced ability to multimerize, and altered distribution pattern in transfected cells when compared with wild-type HOMER2. Interestingly, the Spanish and Chinese frameshift mutations might exert a similar effect at the protein level, leading to truncated mutants with the same Ct aberrant protein tail, thus suggesting that they can share a common mechanism of pathogenesis. Indeed, age-matched patients in both families display quite similar hearing loss phenotypes consisting of early-onset, moderate-to-profound progressive hearing loss. In summary, we have identified the third variant in HOMER2, which is the first one identified in the Spanish population, thus contributing to expanding the mutational spectrum of this gene in other populations, and also to clarifying the genotype–phenotype correlations of DFNA68 hearing loss.

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Role of CASP7 polymorphisms in noise-induced hearing loss risk in Han Chinese population

Scientific Reports ◽

10.1038/s41598-021-81391-5 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Yanmei Ruan ◽

Jinwei Zhang ◽

Shiqi Mai ◽

Wenfeng Zeng ◽

Lili Huang ◽

...

Keyword(s):

Hearing Loss ◽

Chinese Population ◽

Conditional Logistic Regression ◽

Han Chinese ◽

Control Group ◽

Environment Interaction ◽

Noise Induced Hearing Loss ◽

Han Chinese Population ◽

Hearing Thresholds ◽

Increased Risk

AbstractGenetic factors and gene-environment interaction may play an important role in the development of noise induced hearing loss (NIHL). 191 cases and 191 controls were selected by case–control study. Among them, case groups were screened from workers exposed to noise in binaural high-frequency hearing thresholds greater than 25 dB (A). Workers with hearing thresholds ≤ 25 dB (A) in any binaural frequency band were selected to the control group, based on matching factors such as age, exposure time to noise, and operating position. The blood samples from two groups of workers were subjected to DNA extraction and SNP sequencing of CASP3 and CASP7 genes using the polymerase chain reaction ligase detection reaction method. Conditional logistic regression correction was used to analyze the genetic variation associated with susceptibility to NIHL. There was an association between rs2227310 and rs4353229 of the CASP7 gene and the risk of NIHL. Compared with the GG genotype, the CC genotype of rs2227310 reduced the risk of NIHL. Compared with CC genotype, the TT genotype of rs4353229 reduced the risk of NIHL. Workers carrying the rs2227310GG and rs4353229CC genotype had an increased risk of NIHL compared to workers without any high-risk genotype. There were additive interaction and multiplication interaction between CASP7rs2227310 and CNE, and the same interaction between CASP7rs4353229 and CNE. The interaction between the CASP7 gene and CNE significantly increased the risk of NIHL. The genetic polymorphisms of CASP7rs2227310GG and CASP7rs4353229CC were associated with an increased risk of NIHL in Han Chinese population and have the potential to act as biomarkers for noise-exposed workers.

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