Chondrocyte‐specific Smad4 gene conditional knockout results in hearing loss and inner ear malformation in mice

Smad4 is the central intracellular mediator of transforming growth factor‐β (TGF‐β) signaling, which plays crucial roles in tissue regeneration, cell differentiation, embryonic development, and regulation of the immune system. Conventional Smad4 gene knockout results in embryonic lethality, precluding its use in studies of the role of Smad4 in inner ear development. We used chondrocyte‐specific Smad4 knockout mice (Smad4^Co/Co) to investigate the function of Smad4 in inner ear development. Smad4^Co/Co mice were characterized by a smaller cochlear volume, bone malformation, and abnormalities of the osseous spiral lamina and basilar membrane. The development of the hair cells was also abnormal, as evidenced by the disorganized stereocilia and reduced density of the neuronal processes beneath the hair cells. Auditory function tests revealed the homozygous Smad4^Co/Co mice suffered from severe sensorineural hearing loss. Our results suggest that Smad4 is required for inner ear development and normal auditory function in mammals. Developmental Dynamics, 2009. © 2009 Wiley‐Liss, Inc.     

Right-sided microtia and conductive hearing loss with variable expressivity in three generations

Familial cases of microtia and meatal atresia are rare, and both dominant and recessive inheritance have been suggested. We here report a family with right-sided external ear malformations and conductive hearing loss in a grandfather, his daughter and granddaughter. The grandfather and the granddaughter both had microtia and meatal atresia, whereas the daughter had a normal outer ear except for a narrow meatus and auricular appendages. The pedigree suggests autosomal dominant inheritance with variable expressivity.     

Interstitial deletion of 4p15.32p16.3 in a boy with minor anomalies,hearing loss,borderline intelligence,and oligodontia

We describe an 11-year-old boy of Saudi origin with an interstitial deletion in the short arm of chromosome 4 (p15.32p16.3) as determined by G-banding and fluorescent in situ hybridization. His clinical manifestations were similar but not identical to previously reported cases of interstitial deletion in the same chromosomal region, and were not those associated with Wolf-Hirschhorn syndrome. The boy had normal facial characteristics, short stature, minor anomalies of hands and feet, amblyopia of the right eye, bilateral hearing loss, and hypotonia. On developmental testing, he had borderline intelligence, with a severe sensory integration and motor planning disorder, and severe deficits in the communication domain. In addition, he had severe oligodontia affecting his secondary dentition. This finding supports the presence of one or more genes involved in dentition in this chromosomal region. Am. J. Med. Genet. 86:316–320, 1999. © 1999 Wiley-Liss, Inc.     

Mixed hearing loss in Larsen Syndrome

A mixed bilateral hearing loss is described in a child with classical Larsen syndrome. The presence of a residual conductive loss after successful placement of ventilating tubes suggests that the conductive loss is due to an ossicular abnormality. In Larsen syndrome, characterized by multiple joint dislocations and bony malformations, the ossicular joints may also be affected.     

A locus for autosomal dominant progressive non-syndromic hearing loss, DFNA27, is on chromosome 4q12-13.1

We ascertained a large North American family, LMG2, segregating progressive, non-syndromic, sensorineural hearing loss. A genome-wide scan identified significant evidence for linkage (maximum logarithm of the odds (LOD) score = 4.67 at θ  = 0 for D4S398) to markers in a 5.7-cM interval on chromosome 4q12-13.1. The DFNA27 interval spans 8.85 Mb and includes at least 61 predicted and 8 known genes. We sequenced eight genes and excluded them as candidates for the DFNA27 gene.     

Diabetes mellitus and hearing loss: A review

Diabetes (type 2) and sensorineural hearing loss are common health problems manifested with ageing. While both type 1 and type 2 diabetes have been associated with hearing loss, a causal link has been difficult to establish. Individuals with diabetes have twice the incidence of hearing loss compared to those without diabetes and those with prediabetes have a 30% higher rate of hearing loss. Whether hearing loss is associated with diabetes independent of glycemic control remains to be determined. Hearing loss has its own set of risk factors and shares others with diabetes. This review will summarize the complex relationship between diabetes and sensorineural hearing loss.     

Ear anomalies and hearing loss in patients with VACTERL association and the effect of maternal diabetes

VACTERL association is typically defined as the presence of three components among these birth defects: vertebral anomalies, anal atresia, cardiac anomalies, esophageal atresia/tracheoesophageal fistula (EA/TEF), renal anomalies, and limb defects. There is increasing recognition that VACTERL and other recurrent constellations of embryonic development often overlap clinically and might share pathogenesis. We conducted a comprehensive chart review of a large patient population with VACTERL association from two tertiary care centers in California. We included patients with incomplete VACTERL expression, which we denoted as “partial VACTERL” (pVACTERL). We assessed the occurrence of craniofacial (CF) findings in these two groups and the combined cohort. We collected data on potential risk factors and demographic information such as sex, Hispanic ancestry, pregnancy complications, and maternal age. The study included 409 participants, of whom 263 had VACTERL and 146 pVACTERL. CF abnormalities were found in 17.3% of VACTERL patients and 9.4% of pVACTERL patients. In the VACTERL group, ear anomalies were found in 10.2%, microtia in 5.9%, hearing loss (HL) in 13.90%, and orofacial clefts in 3.1%. In the pVACTERL group, ear anomalies were found in 7.2%, microtia in 5.0%, HL in 9.3%, and orofacial cleft in 2.2%. Maternal diabetes significantly increased the risk for HL in VACTERL (odds ratio [OR]: 3.71, 95% confidence interval [CI]: 1.5–7.3) and pVACTERL patients (OR: 6.7, 95% CI: 1.70–23.4). Poorly controlled maternal diabetes significantly increased the risk for all the outcomes in VACTERL patients including CF anomalies (OR: 4.2, 95% CI: 1.9–9.6), ear anomalies (OR: 4.7, 95% CI: 1.8–11.8), microtia (OR: 5.4, 95% CI: 1.7–16.6), and HL (OR: 8.1, 95% CI: 3.4–19.4). Twin status was significantly associated with the occurrence of microtia (p = 0.038) in VACTERL patients. Occurrence of CF features, particularly ear anomalies, microtia, and HL, might be considered as part of phenotypic diversity of VACTERL association. Diabetes and twinning might appear to play a role in increasing the risk for this phenotype in VACTERL association.     

Chromosome imbalances in syndromic hearing loss

The cause of hearing impairment has not been elucidated in a large proportion of patients. We screened by 1-Mb array-based comparative genomic hybridization (aCGH) 29 individuals with syndromic hearing impairment whose clinical features were not typical of known disorders. Rare chromosomal copy number changes were detected in eight patients, four de novo imbalances and four inherited from a normal parent. The de novo alterations define candidate chromosome segments likely to harbor dosage-sensitive genes related to hearing impairment, namely 1q23.3–q25.2, 2q22q23, 6p25.3 and 11q13.2–q13.4. The rare imbalances also present in normal parents might be casually associated with hearing impairment, but its role as a predisposition gene remains a possibility. Our results show that syndromic deafness is frequently associated with chromosome microimbalances (14–27%), and the use of aCGH for defining disease etiology is recommended.     

The immunohistochemical expression pattern of Chk2, p53, p19INK4d,MAGE-A4 and other selected antigens provides new evidence for the premeiotic origin of spermatocytic seminoma

AIMS: Spermatocytic seminoma is a rare germ cell derived tumour of the testis that occurs mainly in older men. We analysed the expression of recently discovered markers for germ cell differentiation and the mitosis-meiosis transition in order to define the antigen profile for diagnostic purposes and to clarify the biology and histogenesis of spermatocytic seminoma. METHODS AND RESULTS: Twenty-five spermatocytic seminomas were examined for immunohistochemical expression of germ cell-specific onco-fetal antigens and proteins involved in regulation of germ cell division, DNA repair and differentiation. The panel included Chk2, p19INK4d, p53, MAGE-A4, KIT, TRA-1-60, neurone-specific enolase and placental-like alkaline phosphatase. Four of these proteins/antigens have never before been investigated in spermatocytic seminoma. Proteins highly expressed in gonocytes and spermatogonia, such as Chk2, MAGE-A4 and neurone-specific enolase, were consistently present in spermatocytic seminoma. Antigens expressed in embryonic germ cells but not in the normal adult testis, e.g. TRA-1-60, were undetectable, with the exception of p53 protein, which was demonstrated in 80% of cases. A proto-oncogene p19INK4d, which is involved in the transition from mitotic to meiotic division in germ cells, was not detected in spermatocytic seminoma. CONCLUSIONS: The investigation provided new information concerning the expression of Chk2, MAGE-A4, neurone-specific enolase and p19INK4d in spermatocytic seminoma. The pattern of expression is highly consistent with the origin of spermatocytic seminoma from a premeiotic germ cell, which has lost embryonic traits and has committed to spermatogenic lineage but has not yet passed the meiotic checkpoint, most probably from the spermatogonium of the adult testis.     

Clinical and genetic features of nonsyndromic autosomal dominant sensorineural hearing loss: KCNQ4 is a gene responsible in Japanese

Sixteen Japanese nonsyndromic autosomal dominant sensorineural hearing loss (ADSNHL) families were investigated clinically as well as genetically. Most families showed postlingual hearing loss. Although the severity of their hearing loss varied, most patients showed mild-moderate sensorineural hearing loss of a progressive nature. Mutation analysis was performed for the MYO7A, KCNQ4, and GJB3 genes, which are known to be responsible for autosomal dominant sensorineural hearing loss. The present study reports that a mutation in KCNQ4, a member of a large family of potassium channel genes, was responsible for ADSNHL in one Japanese family. Received: January 16, 2001 / Accepted: March 15, 2001     

Further evidence for linkage of low-mid frequency hearing impairment to the candidate region on chromosome 4p16.3

We have investigated a three-generation family with an autosomal dominant low-mid frequency hearing loss. Audiograms show consistently a hearing threshold of 50+/-20 db hearing loss (HL) between 250 Hz and 1-2 kHz. Normal hearing level was reached between 3 and 6 kHz in all examined children. Adult patients show an additional hearing impairment (HI) in the mid and higher frequencies that seems to differ from presbyacusis. The HI is always bilateral and symmetrical. Genes causing non-syndromic autosomal-dominant deafness with HI in the low and mid frequencies were previously mapped to chromosome 4p16.3 (DFNA6, DFNA14) and chromosome 5q31 (DFNA1). After exclusion of linkage to DFNA1 on chromosome 5, we mapped the candidate gene region to the DFNA14 and DFNA6 loci, between the genetic markers D4S432 and D4S431, located on chromosome 4. This is a further family in which evident linkage of low-mid frequency HI to the candidate region on chromosome 4p16.3 has been found.     

New gene for autosomal recessive non-syndromic hearing loss maps to either chromosome 3q or 19p

Autosomal recessive non-syndromic hearing loss (ARNSHL) is the most common form of prelingual inherited hearing impairment. A small consanguineous family with this disorder was ascertained through the Institute of Basic Medical Sciences in Madras, India. Conditions such as rubella, prematurity, drug use during pregnancy, perinatal trauma, and meningitis were eliminated by history. Audiometry was performed to confirm severe-to-profound hearing impairment in affected persons. After excluding linkage to known DFNB genes, two genomic DNA pools, one from the affected persons and the other from their non-affected siblings and the parents, were used to screen 165 polymorphic markers evenly spaced across the autosomal human genome. Two regions showing homozygosity-by-descent in the affected siblings were identified on chromosomes 3q21.3-q25.2 and 19p13.3-p13.1, identifying one (or possibly both) as the site of a novel ARNSHL gene. Am. J. Med. Genet. 71:467–471, 1997. © 1997 Wiley-Liss, Inc.     

Susceptibility of the sympathectomized ear to noise-induced hearing loss

Unilaterally sympathectomiced rats were exposed to 100 dB L_eq frequency-modulated noise for I month. Normotensive as well as spontaneously hypertensive animals (with a blood pressure of above 200 mmHg) were investigated. Auditory sensitivity was determined by auditory brainstem responses to 1/3-octave filtered sine waves in the frequency range 0.8–20.0 kHz. In addition, a morphological analysis was carried out. It was found that the sympathetic innervation to the inner ear of the rat originated in, or passed through the ipsilateral superior cervical ganglion. Sympathectomy did not alter pre-exposure hearing thresholds nor influence the size of the noise-induced hearing loss either in 3 or 11 months old hypertensive rats, or in normotensive rats of 11 months. A slightly smaller loss was seen in the sympathectomized side in young normotensive rats. It was concluded that the sympathetic does not exert a protection of the inner ear against functional disturbances in hypertension, neither during basal metabolic condition nor during extreme conditions, i.e. during noxious noise exposure.     

New role of LRP5, associated with nonsyndromic autosomal‐recessive hereditary hearing loss

Human hearing loss is a common neurosensory disorder about which many basic research and clinically relevant questions are unresolved. At least 50% of hearing loss are due to a genetic etiology. Although hundreds of genes have been reported, there are still hundreds of related deafness genes to be found. Clinical, genetic, and functional investigations were performed to identify the causative mutation in a distinctive Chinese family with postlingual nonsyndromic sensorineural hearing loss. Whole‐exome sequencing (WES) identified lipoprotein receptor‐related protein 5 (LRP5), a member of the low‐density lipoprotein receptor family, as the causative gene in this family. In the zebrafish model, lrp5 downregulation using morpholinos led to significant abnormalities in zebrafish inner ear and lateral line neuromasts and contributed, to some extent, to disabilities in hearing and balance. Rescue experiments showed that LRP5 mutation is associated with hearing loss. Knocking down lrp5 in zebrafish results in reduced expression of several genes linked to Wnt signaling pathway and decreased cell proliferation when compared with those in wild‐type zebrafish. In conclusion, the LRP5 mutation influences cell proliferation through the Wnt signaling pathway, thereby reducing the number of supporting cells and hair cells and leading to nonsyndromic hearing loss in this Chinese family.     

Therapeutic effects of carbogen inhalation and lipo-prostaglandin e1 in sudden hearing loss

Purpose: Vascular disorders and viral infections are considered the main causes of sudden hearing loss (SHL), although its pathogenesis remain unclear. Treatments include carbogen inhalation and lipo-prostaglandin E1 (lipo-PGE1), both of which have circulation-enhancing effects. We investigated the effectiveness of carbogen inhalation and lipo-PGE1 in SHL. Materials and Methods: This retrospective review included 202 patients with idiopathic SHL who visited our clinic within 14 days of symptom onset between January 2006 and June 2010. All patients received oral prednisolone for 10 days. Of the 202 patients, 44 received no additional treatment, 106 received additional carbogen inhalation, and 52 received additional lipo-PGE1. Hearing improvement was measured using Siegel's criteria. Results: Overall recovery rates were 67.9% in the carbogen group, 53.8% in the lipo-PGE1 group, and 52.3% in the steroid-only control group (p=0.097). Limited to type 1 and type 2 categories of Sigels's criteria, the carbogen group had a significantly higher recovery rate (53.8%) than the lipo-PGE1 group (26.9%) and the steroid-only control group (38.6%) (p=0.005). Conclusion: Carbogen inhalation added to steroid was a more effective treatment than lipo-PGE1 added to steroid or steroid alone in patients with SHL.     

High frequency of autosomal-recessive DFNB59 hearing loss in an isolated Arab population in Israel

Autosomal-recessive non-syndromic hearing impairment (DFNB) is usually of prelingual onset with a moderate to profound degree of hearing loss. More than 70 DFNB loci have been mapped and ~40 causative genes have been identified. Non-syndromic hearing impairment caused by mutations of DFNB59 (encoding pejvakin) has been described in a couple of families in which affected individuals presented with either auditory neuropathy or hearing loss of cochlear origin. We have identified and clinically evaluated three consanguineous families of Israeli Arab origin with prelingual non-syndromic hearing impairment and absent otoacoustic emissions in a total of eight affected individuals. All the families originate from the same village and bear the same family name. We have identified a c.406C>T (p.R136X) nonsense mutation in the DFNB59 gene in affected individuals from these families. Among the inhabitants of the village, we found an exceptionally high carrier frequency of ~1 in 12 individuals (7/85; 8.2%). The high prevalence of hearing impairment can be explained by a founder effect and the high consanguinity rate among the inhabitants of this village.     

Cell degeneration is not a primary causer for Connexin26 (GJB2) deficiency associated hearing loss

Connexin26 (Cx26, GJB2) mutations can induce congenital deafness and are responsible for ∼50% of nonsyndromic hearing loss in children. Mouse models show that Cx26 deficiency induces cochlear development disorder, hair cell loss, and spiral ganglion (SG) neuron degeneration. Hair cell loss and cell degeneration have been considered as a primary causer responsible for Cx26 deficiency associated hearing loss. In this study, by coincidental examination of cochlear postnatal development with recording of auditory brainstem response (ABR) and hair cell function, we found that occurrence of hearing loss in Cx26 knockout (KO) mice was ahead of hair cell loss and cochlear cell degeneration. ABR was absent at the whole-frequency range (8–40 kHz) after birth. However, cochlear cells including SG neurons had no significant degeneration throughout postnatal development. Severe cochlear hair cell loss and SG neuron degeneration were only visible in middle and basal turns, i.e., in middle and high frequency regions, in the adult Cx26 KO mouse cochlea. Functional tests show that hair cells in Cx26 KO mice functioned normally; outer hair cells retained electromotility. These data suggest that cell degeneration is not a primary causer of Cx26 deficiency associated hearing loss. Some mechanisms other than cell degeneration, such as cochlear development disorders, may play an essential role in this common hereditary deafness.