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1.
Brain Dev ; 2021 Jan 12.
Artigo em Inglês | MEDLINE | ID: mdl-33451880

RESUMO

BACKGROUND: Rapid-onset dystonia-parkinsonism (RDP) is a disease characterized by an abrupt onset of dystonia accompanied by signs of parkinsonism and prominent bulbar symptoms. CASE REPORT: We describe a case of a female patient, born after normal delivery, but diagnosed with mild intellectual disability at age 7. She presented with an abrupt onset of upper limb dystonia and bradykinesia without tremor in parkinsonism, as well as dysarthria and dysphagia caused by prominent bulbar symptoms, at age 9. She had normal findings on brain magnetic resonance imaging, electroencephalography, and blood examination but was diagnosed with a psychogenic disorder. At age 10, she developed left lower limb paroxysmal stiffness with pain, and at 14, she was hospitalized due to lasting paroxysmal symptoms. Whole-exome sequencing was performed for this index case and her parents, and a de novo missense variant c.829G > A, p.Glu277Lys in ATP1A3 was identified. DISCUSSION: This RDP case highlights a rare clinical feature of paroxysmal dystonia that affects the lower left limb and develops after the abrupt onset of permanent dystonia. Currently, there are only three reported RDP cases associated with the same missense mutation, and we summarized the clinical features of all cases including ours, such as onset of age, time for stable, RDP score, relapse and exacerbation. Various symptoms owing to ATP1A3 mutation could develop as ATP1A3-related neurological disorders beyond classical phenotypes such as alternating hemiplegia of childhood (AHC) or RDP. Although RDP is extremely rare during childhood, it is important to understand its clinical characteristics in children.

2.
Am J Med Genet A ; 2020 Dec 10.
Artigo em Inglês | MEDLINE | ID: mdl-33300650

RESUMO

Infantile liver failure syndrome type 1 (ILFS1) is a recently recognized autosomal recessive disorder caused by deleterious mutations in the leucyl-tRNA synthetase 1 gene (LARS1). The LARS1 enzyme is responsible for incorporation of the amino acid leucine during protein polypeptide synthesis. Individuals with LARS1 mutations typically show liver failure from infancy to early childhood during periods of illness or other physiological stress. While 25 patients from 15 families with ILFS1 have been reported in the literature, histological reports from autopsy findings are limited. We report here a premature male neonate who presented with severe intrauterine growth retardation, microcytic anemia, and fulminant liver failure, and who was a compound heterozygote for two novel deleterious mutations in LARS1. An autopsy showed fulminant hepatitis-like hepatocellular injury and fibrogenesis in the liver and a lack of uniformity in skeletal muscle, accompanied by the disruption of striated muscle fibers. Striking dysgenesis in skeletal muscle detected in the present case indicates the effect of LARS1 functional deficiency on the musculature. Whole-exome sequencing may be useful for neonates with unexplained early liver failure if extensive genetic and metabolic testing is inconclusive.

3.
Brain Dev ; 2020 Nov 28.
Artigo em Inglês | MEDLINE | ID: mdl-33261925

RESUMO

AIM: MOGS mutations cause congenital disorders of glycosylation type IIb (CDG-IIb or GCS1-CDG). The specific manifestations caused by the mutations in this gene remain unknown. We aimed to describe the clinical features of CDG- IIb and the effectiveness of urinary oligosaccharide analysis in the diagnosis of CDG- IIb. METHODS: Patient 1 was analyzed with whole-exome sequencing (WES) to identify the causative gene of intractable epilepsy and severe developmental delay. After detecting MOGS mutation in patient 1, we analyzed patients 2 and 3 who were siblings and had clinical features similar to those in patient 1. Urinary oligosaccharide analysis was performed to confirm CDG- IIb diagnosis in patient 1. The clinical features of these patients were analyzed and compared with those in eight published cases. RESULTS: Our three patients presented with early infantile epileptic encephalopathy, generalized hypotonia, hepatic dysfunction and dysmorphic features. In two cases, compound heterozygous mutations in MOGS were identified by WES. Isolation and characterization of the urinary oligosaccharide was performed in one of these cases to confirm the diagnosis of CDG-IIb. Although the isoelectric focusing of transferrin (IEF-T) of serum in this patient was normal, urinary excretion of Hex4 corresponding to Glc3Man was observed by mass spectrometry. CONCLUSION: This report provides clinical manifestations of CDG-IIb with MOGS mutation. CDG-IIb shows a normal IEF profile of serum transferrin and cannot be detected by structural analysis of the patient's glycoproteins. Characterization of urinary oligosaccharides should be considered to detect this disorder.

4.
Brain Dev ; 2020 Nov 25.
Artigo em Inglês | MEDLINE | ID: mdl-33248857

RESUMO

Paroxysmal abnormal eye movement in early infancy is one of the initial symptoms of glucose transporter 1 deficiency syndrome (GLUT1DS). We describe four early infants with transient hypoglycorrhachia presenting with abnormal eye movements. Their symptoms disappeared after the introduction of a ketogenic diet (KD), and their development was normal. Since no variants in SLC2A1 were detected, the CSF-to-blood glucose ratios (C/B) were re-examined, and within normal range. None of the four patients displayed recurrent symptoms after withdrawal from the KD. Because long-term KD has potential adverse effects and could affect the quality of life of patients and their families, re-examination of CSF glucose during late infancy should be considered in the case of absence of the SLC2A1 pathogenic variant.

5.
Genomics ; 2020 Nov 04.
Artigo em Inglês | MEDLINE | ID: mdl-33157260

RESUMO

We report monozygotic twin girls with syndromic intellectual disability who underwent exome sequencing but with negative pathogenic variants. To search for variants that are unrecognized by exome sequencing, high-fidelity long-read genome sequencing (HiFi LR-GS) was applied. A 12-kb copy-neutral inversion was precisely identified by HiFi LR-GS after trio-based variant filtering. This inversion directly disrupted two genes, CPNE9 and BRPF1, the latter of which attracted our attention because pathogenic BRPF1 variants have been identified in autosomal dominant intellectual developmental disorder with dysmorphic facies and ptosis (IDDDFP), which later turned out to be clinically found in the twins. Trio-based HiFi LR-GS together with haplotype phasing revealed that the 12-kb inversion occurred de novo on the maternally transmitted chromosome. This study clearly indicates that submicroscopic copy-neutral inversions are important but often uncharacterized culprits in monogenic disorders and that long-read sequencing is highly advantageous for detecting such inversions involved in genetic diseases.

6.
J Hum Genet ; 2020 Oct 10.
Artigo em Inglês | MEDLINE | ID: mdl-33040083

RESUMO

Pontocerebellar hypoplasia (PCH) is currently classified into 13 subgroups and many gene variants associated with PCH have been identified by next generation sequencing. PCH type 1 is a rare heterogeneous neurodegenerative disorder. The clinical presentation includes early-onset severe developmental delay, progressive motor neuronopathy, and cerebellar and pontine atrophy. Recently two variants in the EXOSC9 gene (MIM: 606180), NM_001034194.1: c.41T>C (p.Leu14Pro) and c.481C>T (p.Arg161*) were identified in four unrelated patients with PCH type 1D (PCH1D) (MIM: 618065). EXOSC9 encodes a component of the exosome complex, which is essential for correct processing and degradation of RNA. We report here two PCH1D families with biallelic EXOSC9 variants: c.239T>G (p.Leu80Arg) and c.484dupA (p.Arg162Lysfs*3) in one family and c.151G>C (p.Gly51Arg) in the other family. Although the patients studied here showed similar clinical features as previously described for PCH1D, relatively greater intellectual development (although still highly restricted) and normal pontine structure were recognized. Our findings expand the clinical consequences of biallelic EXOSC9 variants.

7.
Sci Rep ; 10(1): 17575, 2020 10 16.
Artigo em Inglês | MEDLINE | ID: mdl-33067521

RESUMO

Cyclin-dependent kinase 8 (CDK8) is a member of the CDK/Cyclin module of the mediator complex. A recent study reported that heterozygous missense CDK8 mutations cause a neurodevelopmental disorder in humans. The mechanistic basis of CDK8-related disorder has yet to be delineated. Here, we report 2 patients with de novo missense mutations within the kinase domain of CDK8 along with the results of in vitro and in vivo functional analyses using a zebrafish model. Patient 1 and Patient 2 had intellectual disabilities and congenital anomalies. Exome analyses showed that patient 1 had a heterozygous de novo missense p.G28A variant in the CDK8 (NM_001260.3) gene and patient 2 had a heterozygous de novo missense p.N156S variant in the CDK8 gene. We assessed the pathogenicity of these two variants using cultured-cells and zebrafish model. An in vitro kinase assay of human CDK8 showed that enzymes with a p.G28A or p.N156S substitution showed decreased kinase activity. An in vivo assays of zebrafish overexpression analyses also showed that the p.G28A and p.N156S alleles were hypomorphic alleles. Importantly, the inhibition of CDK8 kinase activity in zebrafish embryos using a specific chemical inhibitor induced craniofacial and heart defects similar to the patients' phenotype. Taken together, zebrafish studies showed that non-synonymous variants in the kinase domain of CDK8 act as hypomorphic alleles causing human congenital disorder.

8.
Hum Mutat ; 41(12): 2119-2127, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-32906213

RESUMO

Chromosomal triplications can be classified into recurrent and nonrecurrent triplications. Most of the nonrecurrent triplications are embedded in duplicated segments, and duplication-inverted triplication-duplication (DUP-TRP/INV-DUP) has been established as one of the mechanisms of triplication. This study aimed to reveal the underlying mechanism of the TRP-DUP-TRP pattern of chromosomal aberrations, in which the appearance of moving averages obtained through array-based comparative genomic hybridization analysis is similar to the shadows of the caldera volcano-like pattern, which were first identified in two patients with neurodevelopmental disabilities. For this purpose, whole-genome sequencing using long-read Nanopore sequencing was carried out to confirm breakpoint junctions. Custom array analysis and Sanger sequencing were also used to detect all breakpoint junctions. As a result, the TRP-DUP-TRP pattern consisted of only two patterns of breakpoint junctions in both patients. In patient 1, microhomologies were identified in breakpoint junctions. In patient 2, more complex architectures with insertional segments were identified. Thus, replication-based mechanisms were considered as a mechanism of the TRP-DUP-TRP pattern.

9.
Biochem Biophys Res Commun ; 529(4): 1033-1037, 2020 Sep 03.
Artigo em Inglês | MEDLINE | ID: mdl-32819561

RESUMO

Takenouchi-Kosaki syndrome (TKS) is an autosomal dominant congenital syndrome, of which pathogenesis is not well understood. Recently, a heterozygous mutation c.1449T > C/p.(Tyr64Cys) in the CDC42 gene, encoding a Rho family small GTPase, has been demonstrated to contribute to the TKS clinical features, including developmental delay with intellectual disability (ID). However, specific molecular mechanisms underlying the neuronal pathophysiology of TKS remain largely unknown. In this study, biochemical analyses revealed that the mutation moderately activates Cdc42. In utero electroporation-based acute expression of Cdc42-Y64C in ventricular zone progenitor cells in embryonic mice cerebral cortex resulted in migration defects and cluster formation of excitatory neurons. Expression the mutant in primary cultured hippocampal neurons caused impaired axon elongation. These data suggest that the c.1449T > C/p.(Tyr64Cys) mutation causes altered CDC42 function and results in defects in neuronal morphology and migration during brain development, which is likely to be responsible for pathophysiology of psychomotor delay and ID in TKS.

10.
J Med Genet ; 2020 Aug 20.
Artigo em Inglês | MEDLINE | ID: mdl-32820033

RESUMO

OBJECTIVE: To determine the potential disease association between variants in LMBRD2 and complex multisystem neurological and developmental delay phenotypes. METHODS: Here we describe a series of de novo missense variants in LMBRD2 in 10 unrelated individuals with overlapping features. Exome sequencing or genome sequencing was performed on all individuals, and the cohort was assembled through GeneMatcher. RESULTS: LMBRD2 encodes an evolutionary ancient and widely expressed transmembrane protein with no known disease association, although two paralogues are involved in developmental and metabolic disorders. Exome or genome sequencing revealed rare de novo LMBRD2 missense variants in 10 individuals with developmental delay, intellectual disability, thin corpus callosum, microcephaly and seizures. We identified five unique variants and two recurrent variants, c.1448G>A (p.Arg483His) in three cases and c.367T>C (p.Trp123Arg) in two cases. All variants are absent from population allele frequency databases, and most are predicted to be deleterious by multiple in silico damage-prediction algorithms. CONCLUSION: These findings indicate that rare de novo variants in LMBRD2 can lead to a previously unrecognised early-onset neurodevelopmental disorder. Further investigation of individuals harbouring LMBRD2 variants may lead to a better understanding of the function of this ubiquitously expressed gene.

12.
Genet Med ; 22(11): 1838-1850, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-32694869

RESUMO

PURPOSE: Nontruncating variants in SMARCA2, encoding a catalytic subunit of SWI/SNF chromatin remodeling complex, cause Nicolaides-Baraitser syndrome (NCBRS), a condition with intellectual disability and multiple congenital anomalies. Other disorders due to SMARCA2 are unknown. METHODS: By next-generation sequencing, we identified candidate variants in SMARCA2 in 20 individuals from 18 families with a syndromic neurodevelopmental disorder not consistent with NCBRS. To stratify variant interpretation, we functionally analyzed SMARCA2 variants in yeasts and performed transcriptomic and genome methylation analyses on blood leukocytes. RESULTS: Of 20 individuals, 14 showed a recognizable phenotype with recurrent features including epicanthal folds, blepharophimosis, and downturned nasal tip along with variable degree of intellectual disability (or blepharophimosis intellectual disability syndrome [BIS]). In contrast to most NCBRS variants, all SMARCA2 variants associated with BIS are localized outside the helicase domains. Yeast phenotype assays differentiated NCBRS from non-NCBRS SMARCA2 variants. Transcriptomic and DNA methylation signatures differentiated NCBRS from BIS and those with nonspecific phenotype. In the remaining six individuals with nonspecific dysmorphic features, clinical and molecular data did not permit variant reclassification. CONCLUSION: We identified a novel recognizable syndrome named BIS associated with clustered de novo SMARCA2 variants outside the helicase domains, phenotypically and molecularly distinct from NCBRS.

13.
J Mass Spectrom ; : e4597, 2020 Jun 19.
Artigo em Inglês | MEDLINE | ID: mdl-32677746

RESUMO

Congenital disorders of glycosylation (CDG) are caused by defects in various genes governing glycoconjugate biosynthesis. Several responsible genes have been identified in the protein N-glycosylation process. Analyses of mucin-type core-1 O-glycoform of apolipoprotein C-III (apoCIII) have recently revealed combined N- and O-glycosylation defects. We applied matrix-assisted laser desorption/ionization mass spectrometry profiling of apoCIII glycoforms to 500 serum samples for CDG screening, and reference values were determined. The content of unglycosylated apoCIII was low in early infancy, indicating that the O-glycan occupancy should be assessed based on age-matched reference values. The samples from patients with mutations in the ALG1, ATP6V0A2, B4GALT1, COG2, GCS1, PGM1, SLC35A2, and TRAPPC11 genes were analyzed. B4GALT1- and TRAPPC11-CDG were accompanied by under-sialylation of O-glycans and are now recognized as combined N- and O-glycosylation disorders.

14.
Gan To Kagaku Ryoho ; 47(7): 1109-1111, 2020 Jul.
Artigo em Japonês | MEDLINE | ID: mdl-32668863

RESUMO

We present the case of a 75-year-old woman who received CapeOX plus Bmab therapy(capecitabine, oxaliplatin, and bevacizumab)after primary excision for an unresectable advanced sigmoid colon cancer with remote metastasis. Pneumatosis intestinalis(i.e., the presence of isolated gas in the abdominal cavity)was revealed accidentally during a periodical imaging examination in the small intestine and transverse colon, albeit no subjective symptoms were reported. Owing to the absence of definitive evidence of pneumatosis intestinalis and gastrointestinal perforation, the patient was diagnosed with idiopathic pneumatosis intestinalis. Bmab was discontinued, and CapeOX therapy alone was continued after follow-up. Approximately 4 months later, pneumatosis intestinalis had completely disappeared. Bmab is a vascular endothelial growth factor antibody with well-known side effect of gastrointestinal-perforation. However, there have been few reports on pneumatosis intestinalis; to our knowledge, there have been no reports on pneumatosis intestinalis associated with colorectal cancer in Japan. Further, the report suggests the need for appropriate and immediate management of pneumatosis intestinalis following diagnosis.


Assuntos
Bevacizumab/efeitos adversos , Neoplasias Colorretais , Pneumatose Cistoide Intestinal/induzido quimicamente , Idoso , Neoplasias Colorretais/tratamento farmacológico , Feminino , Humanos , Japão , Fator A de Crescimento do Endotélio Vascular
15.
Hum Genet ; 139(12): 1555-1563, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-32535809

RESUMO

The chromosomal region critical in Down syndrome has long been analyzed through genotype-phenotype correlation studies using data from many patients with partial trisomy 21. Owing to that, a relatively small region of human chromosome 21 (35.9 ~ 38.0 Mb) has been considered as Down syndrome critical region (DSCR). In this study, microarray-based comparative genomic hybridization analysis identified complex rearrangements of chromosome 21 in a patient manifesting clinical features partially overlapped with that of Down syndrome. Although the patient did not show up-slanting palpebral fissures and single transverse palmar creases, other symptoms were consistent with Down syndrome. Rearrangements were analyzed by whole-genome sequencing using Nanopore long-read sequencing. The analysis revealed that chromosome 21 was fragmented into seven segments and reassembled by six connected points. Among 12 breakpoints, 5 are located within the short region and overlapped with repeated segments. The rearrangement resulted in a maximum gain of five copies, but no region showed loss of genomic copy numbers. Breakpoint-junctions showed no homologous region. Based on these findings, chromoanasynthesis was considered as the mechanism. Although the distal 21q22.13 region was not included in the aberrant regions, some of the genes located on the duplicated regions, SOD1, SON, ITSN1, RCAN1, and RUNX1, were considered as possible candidate genes for clinical features of the patient. We discussed the critical region for Down syndrome, with the literature review.


Assuntos
Cromossomos Humanos Par 21/genética , Cromossomos Humanos/genética , Síndrome de Down/genética , Proteínas Adaptadoras de Transporte Vesicular/genética , Aberrações Cromossômicas , Hibridização Genômica Comparativa/métodos , Subunidade alfa 2 de Fator de Ligação ao Core/genética , Proteínas de Ligação a DNA/genética , Síndrome de Down/fisiopatologia , Feminino , Dosagem de Genes/genética , Estudos de Associação Genética , Humanos , Hibridização in Situ Fluorescente/métodos , Lactente , Análise em Microsséries/métodos , Antígenos de Histocompatibilidade Menor/genética , Proteínas Musculares/genética , Superóxido Dismutase-1/genética , Sequenciamento Completo do Genoma
16.
Epilepsy Res ; 164: 106371, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32485575

RESUMO

We report on familial 5 epilepsy patients with autosomal dominant inheritance of a novel heterozygous NUS1 frameshift mutation. All patients had cerebellar ataxia and tremor. Three patients were diagnosed with childhood absence epilepsy, 1 patient with generalized epilepsy, and 1 patient with parkinsonism without epilepsy. Our cases and previously reported cases with deletions of chromosome 6q22 that include NUS1 share these common symptoms. In a cellular experiment, NUS1 mutation led to a substantial reduction of the protein level of NUS1. NUS1 mutation could contribute to epilepsy pathogenesis and also constitute a distinct syndromic entity with cerebellar ataxia and tremor.

17.
J Hum Genet ; 65(10): 847-853, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32451492

RESUMO

Bardet-Biedl syndrome (BBS) is a rare autosomal recessive disorder characterized by obesity, mental impairment, rod-cone dystrophy, polydactyly, male hypogonadism, and renal abnormalities. This disorder is caused by mutations in BBS1-21. Alström syndrome (AS), caused solely by mutations in ALMS1, is another genetic obesity syndrome clinically similar to BBS. We previously conducted the first nationwide survey of BBS in Japan and found four patients with genetically definite BBS. In this study, exome analyses were performed on new patients whose symptoms fulfilled the diagnostic criteria for BBS. We identified one reported heterozygous mutation in BBS1 (p.R429*) in one patient, two novel mutations (p.L493R and p.H719Y) in BBS20 in a second patient, and one novel mutation (p.Q920*) and one reported mutation (p.R2928*) in ALMS1 in a third patient, who was subsequently diagnosed with AS. The first patient with BBS was previously considered to have digenic heterozygous mutations in BBS1 and BBS4. RT-PCR and long-range genomic PCR analyses identified a new heterozygous mutation in BBS1, the deletion of exons 10 and 11. Thus, this patient was compound heterozygous for mutations in BBS1. Many studies have described digenic heterozygous mutations in BBS. However, undetected mutations might have existed in either one of the mutated genes.

18.
J Hum Genet ; 65(9): 751-757, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32405030

RESUMO

Inborn errors of metabolism can cause epileptic encephalopathies. Biallelic loss-of-function variants in the ITPA gene, encoding inosine triphosphate pyrophosphatase (ITPase), have been reported in epileptic encephalopathies with lack of myelination of the posterior limb of the internal capsule, brainstem tracts, and tracts to the primary visual and motor cortices (MIM:616647). ITPase plays an important role in purine metabolism. In this study, we identified two novel homozygous ITPA variants, c.264-1 G > A and c.489-1 G > A, in two unrelated consanguineous families. The probands had epilepsy, microcephaly with characteristic magnetic resonance imaging findings (T2 hyperintensity signals in the pyramidal tracts of the internal capsule, delayed myelination, and thin corpus callosum), hypotonia, and developmental delay; both died in early infancy. Our report expands the knowledge of clinical consequences of biallelic ITPA variants.

19.
Am J Hum Genet ; 106(5): 596-610, 2020 05 07.
Artigo em Inglês | MEDLINE | ID: mdl-32243864

RESUMO

Weaver syndrome (WS), an overgrowth/intellectual disability syndrome (OGID), is caused by pathogenic variants in the histone methyltransferase EZH2, which encodes a core component of the Polycomb repressive complex-2 (PRC2). Using genome-wide DNA methylation (DNAm) data for 187 individuals with OGID and 969 control subjects, we show that pathogenic variants in EZH2 generate a highly specific and sensitive DNAm signature reflecting the phenotype of WS. This signature can be used to distinguish loss-of-function from gain-of-function missense variants and to detect somatic mosaicism. We also show that the signature can accurately classify sequence variants in EED and SUZ12, which encode two other core components of PRC2, and predict the presence of pathogenic variants in undiagnosed individuals with OGID. The discovery of a functionally relevant signature with utility for diagnostic classification of sequence variants in EZH2, EED, and SUZ12 supports the emerging paradigm shift for implementation of DNAm signatures into diagnostics and translational research.


Assuntos
Anormalidades Múltiplas/genética , Hipotireoidismo Congênito/genética , Anormalidades Craniofaciais/genética , Metilação de DNA , Proteína Potenciadora do Homólogo 2 de Zeste/genética , Deformidades Congênitas da Mão/genética , Deficiência Intelectual/genética , Mutação , Complexo Repressor Polycomb 2/genética , Adolescente , Adulto , Criança , Pré-Escolar , Estudos de Coortes , Feminino , Humanos , Lactente , Masculino , Mosaicismo , Mutação de Sentido Incorreto/genética , Reprodutibilidade dos Testes , Adulto Jovem
20.
Genes (Basel) ; 11(3)2020 03 04.
Artigo em Inglês | MEDLINE | ID: mdl-32143290

RESUMO

MYO6 is known as a genetic cause of autosomal dominant and autosomal recessive inherited hearing loss. In this study, to clarify the frequency and clinical characteristics of hearing loss caused by MYO6 gene mutations, a large-scale genetic analysis of Japanese patients with hearing loss was performed. By means of massively parallel DNA sequencing (MPS) using next-generation sequencing for 8074 Japanese families, we found 27 MYO6 variants in 33 families, 22 of which are novel. In total, 2.40% of autosomal dominant sensorineural hearing loss (ADSNHL) in families in this study (32 out of 1336) was found to be caused by MYO6 mutations. The present study clarified that most cases showed juvenile-onset progressive hearing loss and their hearing deteriorated markedly after 40 years of age. The estimated hearing deterioration was found to be 0.57 dB per year; when restricted to change after 40 years of age, the deterioration speed was accelerated to 1.07 dB per year. To obtain supportive evidence for pathogenicity, variants identified in the patients were introduced to MYO6 cDNA by site-directed mutagenesis and overexpressed in epithelial cells. They were then assessed for their effects on espin1-induced microvilli formation. Cells with wildtype myosin 6 and espin1 co-expressed created long microvilli, while co-expression with mutant constructs resulted in severely shortened microvilli. In conclusion, the present data clearly showed that MYO6 is one of the genes to keep in mind with regard to ADSNHL, and the molecular characteristics of the identified gene variants suggest that a possible pathology seems to result from malformed stereocilia of the cochlear hair cells.

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