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 D. 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

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Abstract

USHER syndrome represents the association of a hearing impairment with retinitis pigmentosa 1 and is the most frequent cause of deaf-blindness in humans. It is inherited as an autosomal recessive trait which is clinically and genetically heterogeneous 2,3 . Some patients show abnormal organization of microtubules in the axoneme of their photoreceptors cells (connecting cilium) 4-6 , nasal ciliar cells 7 and sperm cells 5 , as well as widespread degeneration of the organ of Corti 8 . 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 USH1 9-11 ,USH1B maps to 11q13.5 (ref. 10) and accounts for about 75% of USH1 patients 2,3 . The mouse deafness shaker-1 (shl) mutation has been localized to the homologous murine region 12,13 . 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 (US)
Pages (from-to)60-61
Number of pages2
JournalNature
Volume374
Issue number6517
DOIs
StatePublished - Jan 1 1995

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

ASJC Scopus subject areas

  • 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. https://doi.org/10.1038/374060a0

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 D.; 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, 01.01.1995, 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, MD, 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. https://doi.org/10.1038/374060a0
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 Jan 1;374(6517):60-61. https://doi.org/10.1038/374060a0
Well, Dominique ; Blanchard, Stéphane ; Kaplan, Josseline ; Guilford, Parry ; Gibson, Fernando ; Walsh, James ; Mburu, Philomena ; Varela, Anabel ; Levilliers, Jacqueline ; Weston, Michael D. ; 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 - Walsh, James

AU - Mburu, Philomena

AU - Varela, Anabel

AU - Levilliers, Jacqueline

AU - Weston, Michael D.

AU - Kelley, Phillip M.

AU - Kimberling, William J.

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AU - Larget-Piet, Dominique

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N2 - USHER syndrome represents the association of a hearing impairment with retinitis pigmentosa 1 and is the most frequent cause of deaf-blindness in humans. It is inherited as an autosomal recessive trait which is clinically and genetically heterogeneous 2,3 . Some patients show abnormal organization of microtubules in the axoneme of their photoreceptors cells (connecting cilium) 4-6 , nasal ciliar cells 7 and sperm cells 5 , as well as widespread degeneration of the organ of Corti 8 . 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 USH1 9-11 ,USH1B maps to 11q13.5 (ref. 10) and accounts for about 75% of USH1 patients 2,3 . The mouse deafness shaker-1 (shl) mutation has been localized to the homologous murine region 12,13 . 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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