Autosomal recessive nonsyndromic hearing loss

Nearly all genes for autosomal recessive nonsyndromal inherited hearing loss (ARNSHL) localized thus far cause prelingual severe to profound or profound hearing impairment. Of the 25 reported loci, most have been identified using single consanguineous families. Six of these genes have been cloned and encode a variety of proteins, including ion channels, extracellular matrix components, cytoskeletal components, and proteins essential for synaptic vesicular trafficking. One of these genes appears to be responsible for approximately 50% of all congenital severe to profound or profound hearing loss in many world populations, and mutations in two other genes can lead to either syndromic or nonsyndromic forms of deafness. The identification of additional genes that cause ARNSHL and elucidation of their function will refine our understanding of auditory physiology at the molecular level.     

A gene for autosomal dominant nonsyndromic hereditary hearing impairment maps to 4p16.3

Mapping genes for nonsyndromic hereditary hearing impairmentmay lead to identification of genes that are essential for thedevelopment and preservation of hearing. We studied a familywith autosomal dominant, progressive, low frequency sensorineuralhearing loss. Linkage analysis employing microsateliite polymorphicmarkers revealed a fully linked marker (D4S126) at 4p16.3, agene-rich region containing IT15, the gene for Huntington'sdisease (HD). For D4S126, the logarithm-of-odds (lod) scorewas 3.64 at     

非综合征性耳聋一家系的基因定位

目的：定位1个一级表亲婚配非综合征性耳聋家系的致病基因，为分离该基因奠定基础。方法：先进行X染色体扫查，排除致病基因位于X染色体的可能；随后采用纯合子定位法，进行候选基因分析和常染色体基因组扫查；再对提示与致病基因紧密连锁的位点所在区域进一步分析，确定致病基因所在区域。结果：确认该家系的非综合征性耳聋为常染色体隐性遗传方式，候选基因分析排除25个已知基因是该家系致病基因的可能，而常染色体扫查提示致病基因位于D17S1293附近，进一步分析将其定位于D17S1850和D17S1818之间5．07cM区域。结论：该家系的致病基因定位于17q11.2-12的D17S1850和D17S1818之间5．07cM区域，是新的常染色体隐性遗传非综合征性耳聋致病基因位点。     

Involvement of DFNB59 mutations in autosomal recessive nonsyndromic hearing impairment

In a consanguineous Turkish family, a locus for autosomal recessive nonsyndromic hearing impairment (ARNSHI) was mapped to chromosome 2q31.1-2q33.1. Microsatellite marker analysis in the complete family determined the critical linkage interval that overlapped with DFNB27, for which the causative gene has not yet been identified, and DFNB59, a recently described auditory neuropathy caused by missense mutations in the DFNB59 gene. The 352-amino acid (aa) DFNB59 gene product pejvakin is present in hair cells, supporting cells, spiral ganglion cells, and the first three relays of the afferent auditory pathway. A novel homozygous nonsense mutation (c.499C>T; p.R167X) was detected in the DFNB59 gene, segregating with the deafness in the family. The mRNA derived from the mutant allele was found not to be degraded in lymphocytes, indicating that a truncated pejvakin protein of 166 aa may be present in the affected individuals. Screening of 67 index patients from additional consanguineous Turkish families with autosomal recessive hearing impairment revealed a homozygous missense mutation (c.547C>T; p.R183W) that segregates with the hearing impairment in one family. Furthermore, in a panel of 83 Dutch patients, two additional novel mutations (c.509_512delCACT; p.S170CfsX35 and c.731T>G; p.L244R), which were not present in ethnically matched controls, were found heterozygously. Together, our data indicate that also nonsense mutations in DFNB59 cause nonsyndromic hearing loss, but that mutations in DFNB59 are not a major cause of nonsyndromic hearing impairment in the Turkish and Dutch population.     

Mitochondrial DNA mutations in patients with postlingual, nonsyndromic hearing impairment

Mitochondrial mutations have previously been reported anecdotally in families with maternally inherited, nonsyndromic hearing impairment. To ascertain the contribution of mitochondrial mutations to postlingual but early-onset, nonsyndromic hearing impairment, we screened patients collected from within two different populations (southern Italy and UK) for previously reported mtDNA mutations associated with hearing disorders. Primer extension (SNP analysis) was used to screen for specific mutations, revealing cases of heteroplasmy and its extent. The most frequently implicated tRNA genes, Leu(UUR) and Ser(UCN), were also sequenced in all Italian patients. All tRNA genes were sequenced in those UK patients showing the clearest likelihood of maternal inheritance. Causative mtDNA mutations were found in approximately 5% of patients in both populations, representing almost 10% of cases that were clearly familial. Age of onset, where known, was generally before adulthood, and hearing loss was typically progressive. Haplogroup analysis revealed a possible excess of haplogroup cluster HV in the patients, compared with population controls, but of borderline statistical significance. In contrast, we did not find any of the previously reported mtDNA mutations, nor a significant deviation from haplogroup cluster frequencies typical of the control population, in patients with late adult-onset hearing loss (age-related hearing impairment) from the UK or Finland.     

Autosomal dominant microtia

Microtia (MIM600674) is a congenital malformation which occurs in 1/8000–10000 births. It is characterized by a small, and abnormally shaped pinna. It ranges in severity from a bump of tissue to a partially formed ear cup. Microtia is often associated with atresia of the external auditory canal. Familial microtia with meatal atresia has been reported, either with dominant or recessive inheritance, which makes genetic counselling difficult in sporadic cases. In the present paper, we report the case of a family with congenital microtia and conductive deafness in two generations, suggesting autosomal dominant inheritance with variable expression and incomplete penetrance.     

Comprehensive molecular etiology analysis of nonsyndromic hearing impairment from typical areas in China

Endothelial dysfunction is associated with major causes of morbidity and mortality, as well as numerous age-related conditions. The possibility of preserving or even rejuvenating endothelial function offers a potent means of preventing/treating some of the most fearful aspects of aging such as loss of mental, cardiovascular, and sexual function. Endothelial precursor cells (EPC) provide a continual source of replenishment for damaged or senescent blood vessels. In this review we discuss the biological relevance of circulating EPC in a variety of pathologies in order to build the case that these cells act as an endogenous mechanism of regeneration. Factors controlling EPC mobilization, migration, and function, as well as therapeutic interventions based on mobilization of EPC will be reviewed. We conclude by discussing several clinically-relevant approaches to EPC mobilization and provide preliminary data on a food supplement, Stem-Kine, which enhanced EPC mobilization in human subjects.     

Autosomal dominant optic atrophy associated with hearing impairment and impaired glucose regulation caused by a missense mutation in the WFS1 gene

Autosomal dominant optic atrophy (ADOA) is genetically heterogeneous, with OPA1 on 3q28 being the most prevalently mutated gene. Additional loci are OPA3, OPA4, and OPA5, located at 19q13.2, 18q12.2, and 22q12.1–q13.1, respectively. Mutations in the WFS1 gene, at 4p16.3, are associated with either optic atrophy (OA) as part of the autosomal recessive Wolfram syndrome or with autosomal dominant progressive low frequency sensorineural hearing loss (LFSNHL) without any ophthalmological abnormalities. Linkage and sequence mutation analyses of the ADOA candidate genes OPA1, OPA3, OPA4, and OPA5, including the genes WFS1, GJB2, and GJB6 associated with recessive inherited OA or dominant LFSNHL, were performed. We identified one novel WFS1 missense mutation E864K, c.2590G→A in exon 8 that co‐segregates with ADOA combined with hearing impairment and impaired glucose regulation. This is the first example of autosomal dominant optic atrophy and hearing loss associated with a WFS1 mutation, supporting the notion that mutations in WFS1 as well as in OPA1 may lead to ADOA combined with impaired hearing.     

Mutations in PLS1, encoding fimbrin,cause autosomal dominant nonsyndromic hearing loss

Nonsyndromic hearing loss (NSHL), a common sensory disorder, is characterized by high clinical and genetic heterogeneity (i.e., approximately 115 genes and 170 loci so far identified). Nevertheless, almost half of patients submitted for genetic testing fail to receive a conclusive molecular diagnosis. We used next‐generation sequencing to identify causal variants in PLS1 (c.805G>A, p.[E269K]; c.713G>T, p.[L238R], and c.383T>C, p.[F128S]) in three unrelated families of European ancestry with autosomal dominant NSHL. PLS1 encodes Plastin 1 (also called fimbrin), one of the most abundant actin‐bundling proteins of the stereocilia. In silico protein modeling suggests that all variants destabilize the structure of the actin‐binding domain 1, likely reducing the protein's ability to bind F actin. The role of PLS1 gene in hearing function is further supported by the recent demonstration that Pls1^?/? mice show a hearing loss phenotype similar to that of our patients. In summary, we report PLS1 as a novel gene for autosomal dominant NSHL, suggesting that this gene is required for normal hearing in humans and mice.     

Autosomal dominant erythromelalgia.

We present a kindred of 29 persons affected with erythromelalgia (erythermalgia) in 5 generations. This paper updates the family reported by Burbank et al. [1966]. Patients have symptoms of intermittent intense burning limb pain related to increased skin temperature. No successful treatment has been identified, and the pathogenetic mechanism has not been established. Most affected individuals are female.     

Autosomal dominant pseudoxanthoma elasticum

Two families are described, each with a unique clinical variant of pseudoxanthoma elasticum (PXE) inherited in autosomal dominant fashion. Dominant type I PXE is characterized by a classical flexurally distributed rash, severe and frequent angina of effort, intermittent claudication and hypertension, and a very severe choroidoretinitis, often complicated by blindness. Dominant type II PXE, on the other hand, is a much milder form of the disease, with a macular rash (though identical histological changes), no vascular changes, and a very mild retinal degeneration, which does not progress to either blindness or choroidoretinitis. Younger members of these families often have prominent choroidal vessels. Formal analysis of the two pedigrees and all the pooled genetic data supported the autosomal dominant transmission of both these traits.     

Autosomal dominant lamellar ichthyosis

Five members of two generations of one family were affected with lamellar ichthyosis, suggesting autosomal dominant transmission. The clinical and histopathological characteristics of the cases described here are similar to those reported by Traupe et al. (1984) as autosomal dominant lamellar ichthyosis and thus confirm the existence of this new form of ichthyosis.     

Autosomal dominant endosteal hyperostosis

The first reported Spanish family with autosomal dominant endosteal hyperostosis is presented and two members in two different generations studied. Neurological involvement with sensorineural hearing loss, chronic intracranial hypertension, and mild corticospinal tract abnormalities were found in one case with radiological evidence of progressive bone disease at follow-up. In addition to mild hydrocephalus, CT-scan of the head documented a reduction in size of the posterior fossa and encroachment of the foramen magnum. A pattern of selective increase in the bone fraction of serum alkaline phosphatase was also recorded. This family supports the view that severe forms of endosteal hyperostosis are not confined to the autosomal recessive variant, as individuals with the autosomal dominant form may also show relentless progression to neurological involvement during adulthood.     

Autosomal dominant congenital laryngomalacia

A family is presented in which congenital stridor due to laryngomalacia was evident in 9 individuals through 3 generations. This report confirms the autosomal dominant transmission of at least one type of laryngomalacia.