Defective myosin VIIA gene responsible for Usher syndrome type IB

Dominique Well, Stéphane Blanchard, Josseline Kaplan, Parry Guilford, Fernando Gibson, James Walsh, Philomena Mburu, Anabel Varela, Jacqueline Levilliers, Michael Weston, Phillip M. Kelley, William J. Kimberling, Mariette Wagenaar, Fabienne Levi-Acobas, Dominique Larget-Piet, Arnold Munnich, Karen P. Steel, Steve D M Brown, Christine Petit

Research output: Contribution to journalArticle

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Abstract

USHER syndrome represents the association of a hearing impairment with retinitis pigmentosa1 and is the most frequent cause of deaf-blindness in humans. It is inherited as an autosomal recessive trait which is clinically and genetically heterogeneous2,3. Some patients show abnormal organization of microtubules in the axoneme of their photoreceptors cells (connecting cilium)4-6, nasal ciliar cells7 and sperm cells5, as well as widespread degeneration of the organ of Corti8. Usher syndrome type 1 (USH1) is characterized by a profound congenital sensorineural hearing loss, constant vestibular dysfunction and prepubertal onset of retinitis pigmentosa. Of three different genes responsible for USH19-11,USH1B maps to 11q13.5 (ref. 10) and accounts for about 75% of USH1 patients2,3. The mouse deafness shaker-1 (shl) mutation has been localized to the homologous murine region12,13. Taking into account the cytoskeletal abnormalities in USH patients, the identification of a gene encoding an unconventional myosin as a candidate for shaker-1(ref. 14) led us to consider the human homo-logue as a good candidate for the gene that is defective in USH1B. Here we present evidence that a gene encoding myosin VIIA is responsible for USH1B. Two different premature stop codons, a six-base-pair deletion and two different missense mutations were detected in five unrelated families. In one of these families, the mutations were identified in both alleles. These mutations, which are located at the amino-terminal end of the motor domain of the protein, are likely to result in the absence of a functional protein. Thus USH IB appears as a primary cytoskeletal protein defect. These results implicate the genes encoding other unconventional myosins and their interacting proteins as candidates for other genetic forms of Usher syndrome.

Original languageEnglish
Pages (from-to)60-61
Number of pages2
JournalNature
Volume374
Issue number6517
StatePublished - 1995

Fingerprint

Usher Syndromes
Myosins
Genes
Photoreceptor Connecting Cilium
Mutation
Axoneme
Retinitis
Retinitis Pigmentosa
Cytoskeletal Proteins
Sensorineural Hearing Loss
Nonsense Codon
Deafness
Missense Mutation
Blindness
Hearing Loss
Nose
Microtubules
Base Pairing
Spermatozoa
Proteins

All Science Journal Classification (ASJC) codes

  • General

Cite this

Well, D., Blanchard, S., Kaplan, J., Guilford, P., Gibson, F., Walsh, J., ... Petit, C. (1995). Defective myosin VIIA gene responsible for Usher syndrome type IB. Nature, 374(6517), 60-61.

Defective myosin VIIA gene responsible for Usher syndrome type IB. / Well, Dominique; Blanchard, Stéphane; Kaplan, Josseline; Guilford, Parry; Gibson, Fernando; Walsh, James; Mburu, Philomena; Varela, Anabel; Levilliers, Jacqueline; Weston, Michael; Kelley, Phillip M.; Kimberling, William J.; Wagenaar, Mariette; Levi-Acobas, Fabienne; Larget-Piet, Dominique; Munnich, Arnold; Steel, Karen P.; Brown, Steve D M; Petit, Christine.

In: Nature, Vol. 374, No. 6517, 1995, p. 60-61.

Research output: Contribution to journalArticle

Well, D, Blanchard, S, Kaplan, J, Guilford, P, Gibson, F, Walsh, J, Mburu, P, Varela, A, Levilliers, J, Weston, M, Kelley, PM, Kimberling, WJ, Wagenaar, M, Levi-Acobas, F, Larget-Piet, D, Munnich, A, Steel, KP, Brown, SDM & Petit, C 1995, 'Defective myosin VIIA gene responsible for Usher syndrome type IB', Nature, vol. 374, no. 6517, pp. 60-61.
Well D, Blanchard S, Kaplan J, Guilford P, Gibson F, Walsh J et al. Defective myosin VIIA gene responsible for Usher syndrome type IB. Nature. 1995;374(6517):60-61.
Well, Dominique ; Blanchard, Stéphane ; Kaplan, Josseline ; Guilford, Parry ; Gibson, Fernando ; Walsh, James ; Mburu, Philomena ; Varela, Anabel ; Levilliers, Jacqueline ; Weston, Michael ; Kelley, Phillip M. ; Kimberling, William J. ; Wagenaar, Mariette ; Levi-Acobas, Fabienne ; Larget-Piet, Dominique ; Munnich, Arnold ; Steel, Karen P. ; Brown, Steve D M ; Petit, Christine. / Defective myosin VIIA gene responsible for Usher syndrome type IB. In: Nature. 1995 ; Vol. 374, No. 6517. pp. 60-61.
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AU - Well, Dominique

AU - Blanchard, Stéphane

AU - Kaplan, Josseline

AU - Guilford, Parry

AU - Gibson, Fernando

AU - Walsh, James

AU - Mburu, Philomena

AU - Varela, Anabel

AU - Levilliers, Jacqueline

AU - Weston, Michael

AU - Kelley, Phillip M.

AU - Kimberling, William J.

AU - Wagenaar, Mariette

AU - Levi-Acobas, Fabienne

AU - Larget-Piet, Dominique

AU - Munnich, Arnold

AU - Steel, Karen P.

AU - Brown, Steve D M

AU - Petit, Christine

PY - 1995

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N2 - USHER syndrome represents the association of a hearing impairment with retinitis pigmentosa1 and is the most frequent cause of deaf-blindness in humans. It is inherited as an autosomal recessive trait which is clinically and genetically heterogeneous2,3. Some patients show abnormal organization of microtubules in the axoneme of their photoreceptors cells (connecting cilium)4-6, nasal ciliar cells7 and sperm cells5, as well as widespread degeneration of the organ of Corti8. Usher syndrome type 1 (USH1) is characterized by a profound congenital sensorineural hearing loss, constant vestibular dysfunction and prepubertal onset of retinitis pigmentosa. Of three different genes responsible for USH19-11,USH1B maps to 11q13.5 (ref. 10) and accounts for about 75% of USH1 patients2,3. The mouse deafness shaker-1 (shl) mutation has been localized to the homologous murine region12,13. Taking into account the cytoskeletal abnormalities in USH patients, the identification of a gene encoding an unconventional myosin as a candidate for shaker-1(ref. 14) led us to consider the human homo-logue as a good candidate for the gene that is defective in USH1B. Here we present evidence that a gene encoding myosin VIIA is responsible for USH1B. Two different premature stop codons, a six-base-pair deletion and two different missense mutations were detected in five unrelated families. In one of these families, the mutations were identified in both alleles. These mutations, which are located at the amino-terminal end of the motor domain of the protein, are likely to result in the absence of a functional protein. Thus USH IB appears as a primary cytoskeletal protein defect. These results implicate the genes encoding other unconventional myosins and their interacting proteins as candidates for other genetic forms of Usher syndrome.

AB - USHER syndrome represents the association of a hearing impairment with retinitis pigmentosa1 and is the most frequent cause of deaf-blindness in humans. It is inherited as an autosomal recessive trait which is clinically and genetically heterogeneous2,3. Some patients show abnormal organization of microtubules in the axoneme of their photoreceptors cells (connecting cilium)4-6, nasal ciliar cells7 and sperm cells5, as well as widespread degeneration of the organ of Corti8. Usher syndrome type 1 (USH1) is characterized by a profound congenital sensorineural hearing loss, constant vestibular dysfunction and prepubertal onset of retinitis pigmentosa. Of three different genes responsible for USH19-11,USH1B maps to 11q13.5 (ref. 10) and accounts for about 75% of USH1 patients2,3. The mouse deafness shaker-1 (shl) mutation has been localized to the homologous murine region12,13. Taking into account the cytoskeletal abnormalities in USH patients, the identification of a gene encoding an unconventional myosin as a candidate for shaker-1(ref. 14) led us to consider the human homo-logue as a good candidate for the gene that is defective in USH1B. Here we present evidence that a gene encoding myosin VIIA is responsible for USH1B. Two different premature stop codons, a six-base-pair deletion and two different missense mutations were detected in five unrelated families. In one of these families, the mutations were identified in both alleles. These mutations, which are located at the amino-terminal end of the motor domain of the protein, are likely to result in the absence of a functional protein. Thus USH IB appears as a primary cytoskeletal protein defect. These results implicate the genes encoding other unconventional myosins and their interacting proteins as candidates for other genetic forms of Usher syndrome.

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