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Учебники / Genetic Hearing Loss Willems 2004

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(35). Moreover, a deletion encompassing exon 1 of GJB6 that is the cause of deafness in seven patients from four families carrying another recessive mutation in the GJB2 gene in trans was recently identified (36). Recently a 342-kb deletion in GJB6 was identified (37). The deletion extended distally to GJB2, which remained intact. Twenty-two of the 33 subjects were heterozygous for both the GJB6 and GJB2 mutations. Two subjects were homozygous for this new GJB6 mutation. This deletion is the second most frequent mutation causing prelingual deafness in the Spanish population. These findings suggest that mutations in the complex locus DFNB1, which contains two genes (GJB2 and GJB6), can result in a monogenic or a digenic pattern of inheritance of prelingual deafness (37).

IV. CONNEXINS AND OTHER DISEASES WITH OR WITHOUT HEARING LOSS

Connexins have been found to be mutated in several other diseases. In most of the cases mutated connexins depending on their tissue expression pattern, led to skin diseases with or without hearing loss. In particular, mutations in four connexins have been demonstrated in epidermal disorders. In three of these connexins, certain mutations may also result in syndromic or nonsyndromic sensorineural hearing loss. In addition to skin disorders, peripheral neuropathies may be the result of connexin mutations.

A.Erythrokeratodermas

Erythrokeratodermas represent a group of disorders characterized by the presence of fixed or slowly moving erythematous hyperkeratotic plaques (38). Erythrokeratoderma variabilis [EKV (MIM 133200)] is an autosomal dominant disorder presenting with di use palmoplantar keratoderma and transient red figurata at other epidermal sites. The erythematous patches a ect the whole body but are more often found on the face, buttocks, and extensor surfaces of the limbs. With increasing age, the areas of the body a ected by EKV become more restricted to the palmoplantar epidermis. In a number of families EKV is linked to the chromosomal region 1p34–p35, where a gene cluster of connexins map (39–41). Subsequently, mutations in a ected members from a number of these pedigrees were identified in the gap junction -3 gene [GJB3 (MIM 603324)] encoding connexin 31 (42). Five GJB3 mutations causing EKV have been described throughout the Cx31 protein, occurring in the intracellular, extracellular, and transmembrane domains (43,44). Although EKV in all families described to date is linked to the chromosomal region 1p34–1p35, not all have mutations in GJB3.

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Recently, a missense mutation in GJB4, encoding for the epidermally expressed Cx30.3 and mapping to 1p34–35, was identified in the a ected members of a family with EKV (44). The mutated residue (F137L) lies in the third transmembrane domain of the protein. The same missense mutation has also been demonstrated in GJB3 in another individual with EKV (45). Additional families with EKV that have Cx30.3 mutations have then been identified.

B.Hidrotic Ectodermal Dysplasia

Hidrotic ectodermal dysplasia (HED), or Clouston syndrome (MIM 129500), is inherited as an autosomal dominant disorder characterized by changes in the epidermis and the appendages, including di use palmoplantar keratoderma, nail dystrophy, and sparse scalp and body hair. In addition, hearing impairment of variable degree is also observed in some cases. A first locus for HED was mapped to the long arm of chromosome 13 (q11–q12) in a large kindred of French Canadian descent (46). Successively, the presence of genetic heterogeneity was demonstrated (47–49). Recently, in a study of a group of families a ected by HED, the presence of mutations (G11R or A88V) in GJB6 encoding Cx30 and mapping at HED locus has been demonstrated (50).

C.Vohwinkel Syndrome

Vohwinkel syndrome (MIM 124500) is an autosomal dominant condition classified as a ‘‘mutilating’’ di use keratoderma in which hyperkeratosis may develop around the circumference of the digits at points of flexion, such as the knuckle. These may form constrictions (or pseudoainhum) sometimes leading to autoamputation of the digit. Another classic epidermal feature is a honeycomb pattern of keratoderma with starfish-like keratoses on the knuckles. Mild to moderate sensorineural hearing loss is often associated with the skin disease. A specific missense mutation, named D66H, in the Cx26 gene (GJB2), causes Vohwinkel syndrome (51,52). In one of these families the Vohwinkel pattern of keratoderma was of a mild form and associated with varying types of hearing impairment. Two D66H-heterozy- gous individuals with the keratoderma in this family were also profoundly deaf and had previously been shown to be heterozygous for another Cx26 variant, M34T (9). Mutation R75W has been described in two members of an Egyptian family a ected by a skin disease similar to Vohwinkel syndrome (53). Additional individuals carrying the R75W mutation have been identified presenting with a variable phenotype (54) including a variable degree of severity of the palmoplantar keratoderma. This finding (also noted

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among D66H heterozygotes) may be explained by the presence of other genetic or environmental factors that may modify the disease penetrance.

D.Autosomal Dominant Palmoplantar Keratoderma and High-Frequency Hearing Loss

Autosomal dominant palmoplantar keratoderma and high-frequency hearing loss (MIM 148350) is characterized by a di use palmoplantar hyperkeratosis and high-tone hearing loss. In a family a ected by this disease a missense GJB2 mutation named G59A was identified (55). A heterozygous 3- bp deletion of the residue E42 (E42) has also been associated with deafness and palmoplantar keratoderma (56). As shown in Figure 2, GJB2 mutations leading either to Vohwinkel syndrome or to autosomal dominant palmoplantar keratoderma and high-frequency hearing loss are clustered in the first extracellular domain. This location is the same as that for mutations leading to autosomal dominant deafness alone. Thus, it would be interesting to further investigate why similar mutations located in the same domain of the protein lead to di erent clinical phenotype with or without skin involvement.

E.Peripheral Neuropathy

The identification of a dominant GJB3 mutation, named 66delD, in a family with peripheral neuropathy and sensorineural hearing loss (57) increases to three the number of disorders resulting from GJB3 mutations. The amino residue at position 66 is highly conserved across species and most likely plays a functionally important role also in other connexins. As previously reported, the mutation D66H in GJB2 causes Vohwinkel syndrome (51), whereas 66delD in the gene for another connexin, GJB1 encoding Cx32, results in the peripheral neuropathy disorder X-linked Charcot-Marie-Tooth disease. Some additional Cx32 mutations are also associated with hearing loss in combination with peripheral neuropathy (58).

V.CONCLUSION

Most of the genes for the most common syndromic forms of hearing loss have already been identified as well as some for nonsyndromic forms, including the gene underlying the most common form of NSRD. Among them, connexins play a major role as a number of genes belonging to this family are involved in hearing loss and they have implications in terms of early molecular diagnosis, genetic counseling, and possible prevention. A simple DNA test can now be provided in NSRD cases to ascertain whether or

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not one is a carrier of a common mutated allele within the GJB2 gene, making risk calculations and genetic counseling more accurate. The identification of specific mutations within connexin genes leading either to hearing impairment and/or a skin disease has further confirmed the importance of gap junction intercellular communication in both the epidermis and the inner ear. Moreover, it has revealed unexpected genotype-phenotype correlations that need further investigation. To really understand why some mutations in the same connexin protein cause skin disease whereas others cause hearing impairment, functional studies of these mutants in a ected tissues and normal tissues are required. In this way, it would be possible, for example, to understand why recessive mutations in Cx26, which has a wide tissue distribution, cause only hearing loss, suggesting that, in other tissues, other connexins can compensate for loss of the Cx26 protein. Studies of the role of the di erent connexins in the inner ear will also be greatly facilitated by the development of animal models, which should be useful not only for studying pathophysiology but also for the development of new therapeutic strategies including gene therapy. So far, the only published connexin knockout mice are those for Cx26, which, because of placental failure, result in embryonic lethality at day 9.5 (59). This phenotype is di erent from that observed in humans, in which recessive protein-truncating GJB2 mutations are associated with hearing impairment. Recently, a conditional CX26 and a CX30 knockout mouse model have been reported to the scientific community, but not yet published. The availability of these two new mouse models will give researchers new insights into the function of GJB2 and GJB6, thus assisting the understanding of pathogenetic mechanisms leading to hearing loss and/ or skin involvement and of gap junction biology.

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15

Myosin VI

Nadav Ahituv, Orit Ben-David, and Karen B. Avraham

Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel

Paolo Gasparini

Second University of Naples and Telethon Institute of Genetics and

Medicine, Naples, Italy

I.INTRODUCTION

Movement of cells or their components is a fundamental activity of eukaryotic cells. The segregation of chromosomes, transport of organelles, and movement of ciliated cells are all possible owing to the large repertoire of molecular motors. Three superfamilies of motor proteins exist—myosins, kinesins, and dyneins—all of which convert chemical energy into mechanical work. Myosins are further defined by their ability to bind actin, to hydrolyze adenosine triphosphate (ATP), and to translocate along actin filaments. The function of this group of molecular motors includes many crucial cellular activities such as membrane tra cking, cell locomotion, signal transduction, and vesicle transport (reviewed in Refs. 1,2). Myosins have historically been divided into two groups: the conventional myosins (myosin II), which include the two-headed, filament-forming dimeric myosins of skeletal muscle, smooth muscle cells; and nonmuscle cells; and the unconventional myosins (myosin I, III–XVIII).

Mutations in five myosins lead to human hearing loss. These include myosin IIIA (3), myosin VI (4), myosin VIIA (5–7), MYH9 (8), and myosin XVA (9). Mouse models for three of these human deafness loci exist, and have provided much information regarding the pathophysiology of the inner ear due to mutations in these genes. The shaker 1 (sh1) and shaker 2 (sh2) mice are associated with mutations in myosin VIIa and myosin XVa, respectively

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