Deafness Syndrome Research Articles

Mitochondrial tRNA mutations associated with deafness

Mitochondrial tRNA mutations are one of the important causes of both syndromic and non–syndromic deafness. Of those, syndromic deafness–associated tRNA mutations such as tRNALeu(UUR) 3243A>G are often present in heteroplasmy, while non–syndromic deafness–associated tRNA mutations including tRNASer(UCN) 7445A>G are often in homplasmy or in high levels of heteroplasmy. These tRNA mutations are the primary mutations leading to hearing loss. However, other tRNA mutations such as tRNAThr 15927G>A and tRNASer(UCN) 7444G>A may act in synergy with the primary mitochondrial DNA mutations, modulating the phenotypic manifestation of the primary mitochondrial DNA mutations. Theses tRNA mutations cause structural and functional alteration. A failure in tRNA metabolism caused by these tRNA mutations impaired mitochondrial translation and respiration, thereby causing mitochondr ial dysfunctions responsible for deafness. These data offer valuable information for the early diagnosis, management and treatment of maternally inherited deafness.

Pathogenesis of Paget Disease of Bone

Paget disease of bone (PDB) is a common disease characterized by focal areas of increased and disorganized bone turnover. Some patients are asymptomatic, whereas others develop complications such as pain, osteoarthritis, fracture, deformity, deafness, and nerve compression syndromes. PDB is primarily caused by dysregulation of osteoclast differentiation and function, and there is increasing evidence that this is due, in part, to genetic factors. One of the most important predisposing genes is SQSTM1, which harbors mutations that cause osteoclast activation in 5-20% of PDB patients. Seven additional susceptibility loci for PDB have been identified by genomewide association studies on chromosomes 1p13, 7q33, 8q22, 10p13, 14q32, 15q24, and 18q21. Although the causal variants remain to be discovered, three of these loci contain CSF1, TNFRSF11A, and TM7SF4, genes that are known to play a critical role in osteoclast differentiation and function. Environmental factors are also important in the pathogenesis of PDB, as reflected by the fact that in many countries the disease has become less common and less severe over recent years. The most widely studied environmental trigger is paramyxovirus infection, but attempts to detect viral transcripts in tissues from patients with PDB have yielded mixed results. Although our understanding of the pathophysiology of PDB has advanced tremendously over the past 10years, many questions remain unanswered, such as the mechanisms responsible for the focal nature of the disease and the recent changes in prevalence and severity.

Maternally Inherited Diabetes and Deafness (MIDD) Syndrome Associated with Myoclonus (IN7-1.009)

Objective: Maternally inherited diabetes and deafness (MIDD) syndrome is a rare mitochondrial disorder characterized by progressive sensorineural hearing loss and diabetes mellitus. Case reports also exist of patients with additional clinical features typically associated with mitochondrial disorders, such as retinopathy, seizures, and stroke-like episodes. We present the clinical, imaging, histopathologic and genetic data for a patient diagnosed with MIDD following evaluation for new-onset myoclonus. To our knowledge, this is the first case to describe MIDD syndrome in association with myoclonus. Background MIDD syndrome is a mitochondrial genetic disorder caused by a heteroplasmic A3243G transition of mtDNA. The same mutation has also been associated with mitochondrial encephalopathy, lactic acidosis and stroke-like episodes (MELAS). It has not been previously associated with myoclonus. Design/Methods: We report the clinical characteristics of a patient diagnosed with MIDD syndrome after initially seeking medical attention for myoclonus, and present the results of a comprehensive literature review. Results: A 57-year-old man developed intermittent myoclonic jerks in his right arm. He had a past history of sensorineural hearing loss developing in his late 20s, and diabetes mellitus developing in his 30s. On exam, he was found to have subtle proximal muscle weakness, as well as peripheral neuropathy. EEG demonstrated rare generalized spike-and-wave discharges. He was started on valproic acid, with resolution of myoclonus. Subsequently, a muscle biopsy demonstrated ragged-red fibers. Genetic testing confirmed the A3243G mtDNA mutation. Given his clinical picture, a diagnosis of MIDD syndrome was established. Conclusions: MIDD syndrome should be considered in patients presenting with a clinical syndrome of sensorineural hearing loss and diabetes mellitus. Additional features of mitochondrial disorders, such as myopathy, neuropathy, and myoclonus may be present. Valproic acid may be an effective treatment of myoclonus. In addition, treatment with coenzyme Q10 may be of modest benefit in slowing progression of neurologic deterioration. Disclosure: Dr. Blondin has nothing to disclose. Dr. Vortmeyer has nothing to disclose. Dr. Tokuno has nothing to disclose.

Maternally Inherited Diabetes and Deafness (MIDD) Syndrome Associated with Myoclonus (P07.148)

Maternally Inherited Diabetes and Deafness (MIDD) Syndrome Associated with Myoclonus (P07.148)

Abstract 2221: Dimerization and DNA binding specificities unravelled by the structure of MITF

Abstract The regulatory protein MITF (microphthalmia associated transcription factor) is essential for melanocyte development and acts as a master regulator of this cell type. Mice carrying loss-of-function mutations in Mitf lack melanocytes altogether and in humans, MITF mutations result in the pigmentation and deafness syndromes Waardenburg and Tietz. In melanoma, MITF plays a critical role as a lineage-survival oncogene and may act as a molecular switch downstream of the Braf pathway, determining whether the cells proliferate or form metastasis. Here we describe the crystal structure of MITF in presence and absence of DNA and use complementary functional experiments to show that Isoleucine 212 of the basic region is critical for discriminating between target sequences. The structures also reveal a kink between the second helix and the Leucine Zipper of MITF which has not been described in other related proteins. This kink is due to a shift in the heptad repeats of the Zipper region and is important for selection of dimerization partners. Our results provide new and important insights into the mechamisms of MITF mediated transcription regulation. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2221. doi:1538-7445.AM2012-2221

A deaf mother and son with diabetes and renal failure.

Chronic renal failure is a well-known complication of long-standing diabetes. Moreover, audiological abnormalities are a common feature of patients with end-stage renal disease. Severe deafness, however, is not a typical symptom in most patients with chronic renal failure and likewise in patients with diabetes mellitus. In this case report, we describe a young patient with insulin-dependant diabetes mellitus, severe deafness requiring hearing aid and chronic renal failure outlining typical clinical features of the maternally inherited diabetes with deafness syndrome. Genetic testing confirmed the presence of the m.3243A>G mutation.

RpgrORF15Connects to the Usher Protein Network through Direct Interactions with Multiple Whirlin Isoforms

Mutations in the retinitis pigmentosa GTPase regulator (RPGR) gene are a frequent cause of X-linked retinitis pigmentosa. The RPGR transcript undergoes complex alternative splicing to express both constitutive (Rpgr(ex1-19)) and Rpgr(ORF15) variants. Because functional studies of Rpgr suggest a role in intracellular protein trafficking through the connecting cilia, the goal of this study was to identify potential binding partners for Rpgr(ORF15) and to identify the domains on whirlin necessary for Rpgr binding. The C-terminus of mouse Rpgr(ORF15) was used as bait in a yeast two-hybrid system. Whirlin expression was analyzed using RT-PCR and Western blot analysis. Protein-protein interactions were confirmed using in vitro binding assays and coimmunoprecipitation. Subcellular colocalization was analyzed using immunohistochemistry on retinal cryosections. Yeast two-hybrid analysis identified whirlin, a PDZ-scaffold protein, as a putative binding partner for Rpgr(ORF15). The RPGR(ORF15)-whirlin interaction was confirmed using in vitro binding assays and coimmunoprecipitation from retinal tissue, and both proteins were shown to colocalize in the photoreceptor connecting cilia in vivo. Results from RT-PCR, Western blot analysis, and immunocytochemistry demonstrated that whirlin expressed multiple isoforms in photoreceptors with variable subcellular localization. Whirlin expression has been reported in photoreceptors and cochlear hair cells, and mutations in whirlin cause Usher syndrome (USH2D) and nonsyndromic congenital deafness (DFNB31). Because mutations in the 5' end of whirlin are associated with the syndromic phenotype associated with USH2D, the identification of novel N-terminal isoforms in the retina and a novel RPGR(ORF15)-whirlin interaction provide a potential mechanism for the retinal phenotype observed in USH2D.

Age-related functional and structural retinal modifications in the Igf1−/− null mouse

BackgroundMutations in the gene encoding human insulin-like growth factor-I (IGF-I) cause syndromic neurosensorial deafness. To understand the precise role of IGF-I in retinal physiology, we have studied the morphology and electrophysiology of the retina of the Igf1−/− mice in comparison with that of the Igf1+/− and Igf1+/+ animals during aging. MethodsSerological concentrations of IGF-I, glycemia and body weight were determined in Igf1+/+, Igf1+/− and Igf1−/− mice at different times up to 360days of age. We have analyzed hearing by recording the auditory brainstem responses (ABR), the retinal function by electroretinographic (ERG) responses and the retinal morphology by immunohistochemical labeling on retinal preparations at different ages. ResultsIGF-I levels are gradually reduced with aging in the mouse. Deaf Igf1−/− mice had an almost flat scotopic ERG response and a photopic ERG response of very small amplitude at postnatal age 360days (P360). At the same age, Igf1+/− mice still showed both scotopic and photopic ERG responses, but a significant decrease in the ERG wave amplitudes was observed when compared with those of Igf1+/+ mice. Immunohistochemical analysis showed that P360 Igf1−/− mice suffered important structural modifications in the first synapse of the retinal pathway, that affected mainly the postsynaptic processes from horizontal and bipolar cells. A decrease in bassoon and synaptophysin staining in both rod and cone synaptic terminals suggested a reduced photoreceptor output to the inner retina. Retinal morphology of the P360 Igf1+/− mice showed only small alterations in the horizontal and bipolar cell processes, when compared with Igf1+/+ mice of matched age. ConclusionsIn the mouse, IGF-I deficit causes an age-related visual loss, besides a congenital deafness. The present results support the use of the Igf1−/− mouse as a new model for the study of human syndromic deaf-blindness.

Venous malformations of the temporal bone are a common feature in CHARGE syndrome

CHARGE (Coloboma of the eye, Heart defects, Atresia of the choanae, Retardation of growth and/or development, Genital and/or urinary abnormalities, and Ear abnormalities and/or deafness) syndrome is a genetic disorder with prominent otolaryngologic features including choanal atresia and inner ear malformations. Recent experience with venous malformations during cochlear implant surgery prompted this study to define the spectrum of venous abnormalities in CHARGE and their surgical implications in otology. Retrospective review of medical and radiologic records from databases of patients with CHARGE syndrome from three tertiary care academic medical centers. Eighteen patients with CHARGE for whom temporal bone CT scans were available were included in the review. Venous anomalies of the temporal bone were present in 10 of 18 (56%) patients. The most common were large emissary veins (n = 5). In two of these cases, these veins were associated with an ipsilateral a hypoplastic sigmoid sinus or jugular foramen. Other abnormalities included an aberrant petrosal sinus, venous lakes in proximity to the lateral venous sinus, condylar canal veins, and jugular bulb abnormalities, including a high riding bulb obscuring the round window niche and a dehiscent jugular bulb. In four of six patients undergoing cochlear implantation, the course of the aberrant vessel necessitated a change in the surgical approach, either during mastoidectomy or placement of the cochleostomy. Temporal bone venous abnormalities are a common feature in CHARGE syndrome. The pattern of venous abnormality suggests that there is a failure of the sigmoid sinus/jugular bulb to fully develop, resulting in persistence of emissary veins. Recognition of these abnormal venous structures during otologic surgery is critical to avoiding potentially catastrophic bleeding.

The Mind Behind the Message: Advancing Theory‐of‐Mind Scales for Typically Developing Children, and Those With Deafness, Autism, or Asperger Syndrome

Children aged 3-12 years (n = 184) with typical development, deafness, autism, or Asperger syndrome took a series of theory-of-mind (ToM) tasks to confirm and extend previous developmental scaling evidence. A new sarcasm task, in the format of H. M. Wellman and D. Liu's (2004) 5-step ToM Scale, added a statistically reliable 6th step to the scale for all diagnostic groups. A key previous finding, divergence in task sequencing for children with autism, was confirmed. Comparisons among diagnostic groups, controlling age, and language ability, showed that typical developers mastered the 6 ToM steps ahead of each of the 3 disabled groups, with implications for ToM theories. The final (sarcasm) task challenged even nondisabled 9-year-olds, demonstrating the new scale's sensitivity to post-preschool ToM growth.

Superficial siderosis of the central nervous system: a rare cause of dementia with therapeutic consequences

A 75-year-old patient was evaluated for dementia. His past medical history included an ischaemic cardiomyopathy treated with aspirin daily. His neurological examination showed mild ataxia syndrome and central deafness. The neuropsychological examination did not suggest Alzheimer's disease. No specific aetiology was found from biological investigations, but MRI scans revealed a superficial siderosis, which was further confirmed with CSF exams. This case highlights the interest of MRI with echo-gradient-T2 weighted sequences in patients investigated for memory disorders. Once the diagnosis is known, specific preventive measures have to be taken: searching for a treatable source of bleeding and the interruption of antiplatelet aggregation or anticoagulant treatments.

Molecular and hereditary mechanisms of sensorineural hearing loss with focus on selected endocrinopathies

Hearing loss is one of the most widespread sensory disorders. The incidence of deafness in general population is 1:1000 newborns. About one half of the cases of the congenital sensorineural hearing loss (SNHL) is inherited. Recessive mutations in the gap junction beta 2 (GJB2) gene are the most common genetic causes of the nonsyndromic SNHL. The GJB2 encodes a protein connexin 26 which forms a subunit of gap junction essential for the correct function of the inner ear. The syndromic SNHL is associated with a wide range of other symptoms, which encompass also dysfunctions of endocrine organs. The Pendred syndrome associated with the hearing impairment is characterized by a prelingual, bilateral sever to profound SNHL, goiter, and iodine organification defect. It is an autosomal recessive disorder, which develops due to mutations in pendrin, an anion channel encoded by SLC26A4 gene. Another important type of syndromic hearing loss is the Maternally Inherited Diabetes and Deafness syndrome, which is caused by several mitochondrial DNA mutations. These mutations are clinically manifested by a hearing impairment with development of the diabetes in the adult age. Hearing impairment occurs during puberty when sensation of high frequency tones is affected following with further progress to profound bilateral sensorineural hearing impairment in the whole frequency range. This review deals with the molecular mechanisms of common genetic causes of the hereditary SNHL along with the selected endocrinopathies emphasizing that the DNA analyses along with the functional studies significantly contribute to the early SNHL diagnosis followed by personalized therapy and genetic counseling.

Pore Width of Disease-Causing Connexin26 Containing Channels

Many point mutations of the gap junction protein connexin26 (Cx26) cause nonsyndromic or syndromic deafness. Some of these mutants form functional channels (Cx26deaf). Most Cx26 in the cochlea exists in heteromeric channels along with connexin30 (Cx30). Using a liposome-based assay of channel activity, we explored (a) the permeability of homomeric hemichannels composed of a Cx26deaf alone and of heteromeric hemichannels composed of both Cx26deaf and wild-type Cx30 (Cx26deaf/Cx30) to sucrose, raffinose, iohexol (NycodenzTM) and diatrizoate (HypaqueTM), and (b) concentration dependence of block of the permeability pathway by alpha-cyclodextrin [1-3]. These studies assess the permeability properties of open channels, and do not report differences in channel gating. None of the channels were permeable to diatrizoate, which is smaller than iohexol but negatively charged; all other compounds are uncharged. Consistent with earlier work, the pores of heteromeric Cx26/Cx30 channels (and most Cx26deaf/Cx30 channels) were more restrictive than either homomeric counterpart, a property shown to correlate with selectivity among signaling molecules [1-5]. In heteromeric channels, the data suggest that Cx26deaf mutations G12R and V95M dramatically narrow the pore relative to Cx26/Cx30, and T8M, V84L and N206S widen it to increasing degrees. G12R, V84L and N206S homomeric channels were less restrictive than homomeric Cx26 channels. T8 and G12 have high probability of being pore lining [6-7]. The other mutation sites are not positioned to directly interact with permeants, so likely exert their effects by other mechanisms. Support: R01NS056509 & R21DC07470.1. Locke, D. J. Biol. Chem. 279:228832. Harris, AL. in: Gap Junctions (ed. R. Werner) p.60, IOS Press3. Bevans, C. Biophys. J. 68:204a4. Ayad, WA. J. Biol. Chem. 281:167275. Bevans, C. J. Biol. Chem. 273:28086. Kwon, TK. J. Gen. Physiol. (in press)7. Oh, S. J. Physiol. 586:2445

Periodontal management in Paget′s disease: Case presentation and a brief review of literature

Paget's disease of bone is a common condition characterized by increased and disorganized bone turnover which can affect one or several bones throughout the skeleton. These abnormalities disrupt normal bone architecture and lead to various complications such as bone pain, osteoarthritis, pathological fracture, bone deformity, deafness, and nerve compression syndromes. Genetic factors and environmental factors like paramyxovirus infection have been implicated in etiology. This is a case report of a patient who presented with Paget's disease and the periodontal surgical management, after the pretreatment was employed with diagnostic procedures like computed tomography and serum alkaline phosphatase tests.

A novel mutation in the MITF may be digenic with GJB2 mutations in a large Chinese family of Waardenburg syndrome type II

Waardenburg syndrome type II (WS2) is associated with syndromic deafness. A subset of WS2, WS2A, accounting for approximately 15% of patients, is attributed to mutations in the microphthalmia-associated transcription factor (MITF) gene. We examined the genetic basis of WS2 in a large Chinese family. All 9 exons of the MITF gene, the single coding exon (exon 2) of the most common hereditary deafness gene GJB2 and the mitochondrial DNA (mtDNA) 12S rRNA were sequenced. A novel heterozygous mutation c.[742_743delAAinsT;746_747delCA] in exon 8 of the MITF gene co-segregates with WS2 in the family. The MITF mutation results in a premature termination codon and a truncated MITF protein with only 247 of the 419 wild type amino acids. The deaf proband had this MITF gene heterozygous mutation as well as a c.[109G>A]+[235delC] compound heterozygous pathogenic mutation in the GJB2 gene. No pathogenic mutation was found in mtDNA 12S rRNA in this family. Thus, a novel compound heterozygous mutation, c.[742_743delAAinsT;746_747delCA] in MITF exon 8 was the key genetic reason for WS2 in this family, and a digenic effect of MITF and GJB2 genes may contribute to deafness of the proband.

Connexin 26 (GJB2) mutations in keratitis–ichthyosis–deafness syndrome presenting with squamous cell carcinoma

Connexin 26 (<i>GJB2</i>) mutations in keratitis–ichthyosis–deafness syndrome presenting with squamous cell carcinoma

GJB2 Gene Mutations in Syndromic Skin Diseases with Sensorineural Hearing Loss.

The GJB2 gene is located on chromosome 13q12 and it encodes the connexin 26, a transmembrane protein involved in cell-cell attachment of almost all tissues. GJB2 mutations cause autosomal recessive (DFNB1) and sometimes dominant (DFNA3) non-syndromic sensorineural hearing loss. Moreover, it has been demonstrated that connexins are involved in regulation of growth and differentiation of epidermis and, in fact, GJB2 mutations have also been identified in syndromic disorders with hearing loss associated with various skin disease phenotypes. GJB2 mutations associated with skin disease are, in general, transmitted with a dominant inheritance pattern. Nonsyndromic deafness is caused prevalently by a loss-of-function, while literature evidences suggest for syndromic deafness a mechanism based on gain-of-function. The spectrum of skin manifestations associated with some mutations seems to have a very high phenotypic variability. Why some mutations can lead to widely varying cutaneous manifestations is poorly understood and in particular, the reason why the skin disease-deafness phenotypes differ from each other thus remains unclear. This review provides an overview of recent findings concerning pathogenesis of syndromic deafness imputable to GJB2 mutations with an emphasis on relevant clinical genotype-phenotype correlations. After describing connexin 26 fundamental characteristics, the most relevant and recent information about its known mutations involved in the syndromic forms causing hearing loss and skin problems are summarized. The possible effects of the mutations on channel expression and function are discussed.

The Cx26-G45E mutation displays increased hemichannel activity in a mouse model of the lethal form of keratitis-ichthyosis-deafness syndrome

Mutations in the GJB2 gene (Cx26) cause deafness in humans. Most are loss-of-function mutations and cause nonsyndromic deafness. Some mutations produce a gain of function and cause syndromic deafness associated with skin disorders, such as keratitis-ichthyosis-deafness syndrome (KIDS). Cx26-G45E is a lethal mutation linked to KIDS that forms constitutively active connexin hemichannels. The pathomechanism(s) by which mutant Cx26 hemichannels perturb normal epidermal cornification are poorly understood. We created an animal model for KIDS by generating an inducible transgenic mouse expressing Cx26-G45E in keratinocytes. Cx26-G45E mice displayed reduced viability, hyperkeratosis, scaling, skin folds, and hair loss. Histopathology included hyperplasia, acanthosis, papillomatosis, increased cell size, and osteal plugging. These abnormalities correlated with human KIDS pathology and were associated with increased hemichannel currents in transgenic keratinocytes. These results confirm the pathogenic nature of the G45E mutation and provide a new model for studying the role of aberrant connexin hemichannels in epidermal differentiation and inherited connexin disorders.

Complete Screening of 50 Patients with CHARGE Syndrome for Anomalies in the CHD7 Gene Using a Denaturing High-Performance Liquid Chromatography–Based Protocol : New Guidelines and a Proposal for Routine Diagnosis

Ocular coloboma, heart malformation, choanal atresia, retardation of growth and/or development, genital hypoplasia, and ear anomalies associated with deafness (CHARGE) syndrome is a rare, usually sporadic, autosomal dominant disorder, caused by mutations within the CHD7 (chromodomain helicase DNA-binding protein 7) gene, in nearly 70% of cases. Because human CHD7 is relatively large (38 exons encoding a 300-kDa protein), genetic analysis requires cost-effective and time-consuming techniques. Herein, we propose an alternative screening method to quickly detect CHD7 mutations using mainly denaturing high-performance liquid chromatography. The entire coding region with exon-intron boundaries was amplified under the same experimental conditions. Each amplicon of the same CHD7 region was subjected to denaturing high-performance liquid chromatography analysis, and resulting chromatograms were compared within small series of patients. Because a CHD7 mutation differs generally from one patient to another, corresponding chromatograms exhibited a unique pattern that is significantly different from common polymorphisms. Only amplicons exhibiting a unique profile were subjected to DNA sequencing analysis. Intragenic rearrangements were investigated with only nine multiplex PCRs. In conclusion, using our protocol, we can quickly detect the right containing mutation amplicon and we provide a robust, rapid, and cheaper method to screen CHD7 microrearrangements or an entire deletion.

Unique phenotype in a patient with CHARGE syndrome

CHARGE is a phenotypically heterogeneous autosomal dominant disorder recognized as a cohesive syndrome since the identification of CHD7 as a genetic etiology. Classic features include: Coloboma, Heart defects, Atresia choanae, Retarded growth and development, Genitourinary abnormalities, and Ear anomalies and/or deafness. With greater accessibility to genetic analysis, a wider spectrum of features are emerging, and overlap with disorders such as DiGeorge syndrome, Kallmann syndrome, and Hypoparathyroidism Sensorineural Deafness and Renal Disease syndrome, is increasingly evident. We present a patient with a unique manifestation of CHARGE syndrome, including primary hypoparathyroidism and a limb anomaly; to our knowledge, he is also the first CHARGE subject reported with bilateral multicystic dysplastic kidneys. Furthermore, with structural modeling and murine expression studies, we characterize a putative CHD7 G744S missense mutation. Our report continues to expand the CHARGE phenotype and highlights that stringent fulfillment of conventional criteria should not strictly guide genetic analysis.