MYO3A Causes Human Dominant Deafness and Interacts with Protocadherin 15-CD2 Isoform

M'hamed Grati, Denise Yan, Manmeet H. Raval, Tom Walsh, Qi Ma, Imen Chakchouk, Abhiraami Kannan-Sundhari, Rahul Mittal, Saber Masmoudi, Susan H. Blanton, Mustafa Tekin, Mary Claire King, Christopher Yengo, Xue Zhong Liu

Research output: Contribution to journalArticle

7 Citations (Scopus)

Abstract

Hereditary hearing loss (HL) is characterized by both allelic and locus genetic heterogeneity. Both recessive and dominant forms of HL may be caused by different mutations in the same deafness gene. In a family with post-lingual progressive non-syndromic deafness, whole-exome sequencing of genomic DNA from five hearing-impaired relatives revealed a single variant, p.Gly488Glu (rs145970949:G>A) in MYO3A, co-segregating with HL as an autosomal dominant trait. This amino acid change, predicted to be pathogenic, alters a highly conserved residue in the motor domain of MYO3A. The mutation severely alters the ATPase activity and motility of the protein in vitro, and the mutant protein fails to accumulate in the filopodia tips in COS7 cells. However, the mutant MYO3A was able to reach the tips of organotypic inner ear culture hair cell stereocilia, raising the possibility of a local effect on positioning of the mechanoelectrical transduction (MET) complex at the stereocilia tips. To address this hypothesis, we investigated the interaction of MYO3A with the cytosolic tail of the integral tip-link protein protocadherin 15 (PCDH15), a core component of MET complex. Interestingly, we uncovered a novel interaction between MYO3A and PCDH15 shedding new light on the function of myosin IIIA at stereocilia tips. We identified a novel mutation in the motor-head of MYO3A causing dominant non-syndromic deafness. The mutation severely alters the ATPase activity and motility of the protein. The mutant protein fails to accumulate in filopodia tips in COS7 cells, but was able to reach explant hair cell stereocilia tips. We also found that MYO3A interacts with integral tip-link protein protocadherin 15 (PCDH15), which led us to speculate about a local dominant effect of mutant MYO3A on MET complex positioning.

Original languageEnglish (US)
Pages (from-to)481-487
Number of pages7
JournalHuman mutation
Volume37
Issue number5
DOIs
StatePublished - May 1 2016

Fingerprint

Stereocilia
Deafness
Protein Isoforms
Molecular Motor Proteins
Hearing Loss
Mutation
Pseudopodia
Mutant Proteins
Adenosine Triphosphatases
Exome
Genetic Heterogeneity
Inner Ear
Myosins
DNA Sequence Analysis
Tongue
Hearing
Tail
Cell Culture Techniques
Head
Amino Acids

All Science Journal Classification (ASJC) codes

  • Genetics
  • Genetics(clinical)

Cite this

Grati, M., Yan, D., Raval, M. H., Walsh, T., Ma, Q., Chakchouk, I., ... Liu, X. Z. (2016). MYO3A Causes Human Dominant Deafness and Interacts with Protocadherin 15-CD2 Isoform. Human mutation, 37(5), 481-487. https://doi.org/10.1002/humu.22961
Grati, M'hamed ; Yan, Denise ; Raval, Manmeet H. ; Walsh, Tom ; Ma, Qi ; Chakchouk, Imen ; Kannan-Sundhari, Abhiraami ; Mittal, Rahul ; Masmoudi, Saber ; Blanton, Susan H. ; Tekin, Mustafa ; King, Mary Claire ; Yengo, Christopher ; Liu, Xue Zhong. / MYO3A Causes Human Dominant Deafness and Interacts with Protocadherin 15-CD2 Isoform. In: Human mutation. 2016 ; Vol. 37, No. 5. pp. 481-487.
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abstract = "Hereditary hearing loss (HL) is characterized by both allelic and locus genetic heterogeneity. Both recessive and dominant forms of HL may be caused by different mutations in the same deafness gene. In a family with post-lingual progressive non-syndromic deafness, whole-exome sequencing of genomic DNA from five hearing-impaired relatives revealed a single variant, p.Gly488Glu (rs145970949:G>A) in MYO3A, co-segregating with HL as an autosomal dominant trait. This amino acid change, predicted to be pathogenic, alters a highly conserved residue in the motor domain of MYO3A. The mutation severely alters the ATPase activity and motility of the protein in vitro, and the mutant protein fails to accumulate in the filopodia tips in COS7 cells. However, the mutant MYO3A was able to reach the tips of organotypic inner ear culture hair cell stereocilia, raising the possibility of a local effect on positioning of the mechanoelectrical transduction (MET) complex at the stereocilia tips. To address this hypothesis, we investigated the interaction of MYO3A with the cytosolic tail of the integral tip-link protein protocadherin 15 (PCDH15), a core component of MET complex. Interestingly, we uncovered a novel interaction between MYO3A and PCDH15 shedding new light on the function of myosin IIIA at stereocilia tips. We identified a novel mutation in the motor-head of MYO3A causing dominant non-syndromic deafness. The mutation severely alters the ATPase activity and motility of the protein. The mutant protein fails to accumulate in filopodia tips in COS7 cells, but was able to reach explant hair cell stereocilia tips. We also found that MYO3A interacts with integral tip-link protein protocadherin 15 (PCDH15), which led us to speculate about a local dominant effect of mutant MYO3A on MET complex positioning.",
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Grati, M, Yan, D, Raval, MH, Walsh, T, Ma, Q, Chakchouk, I, Kannan-Sundhari, A, Mittal, R, Masmoudi, S, Blanton, SH, Tekin, M, King, MC, Yengo, C & Liu, XZ 2016, 'MYO3A Causes Human Dominant Deafness and Interacts with Protocadherin 15-CD2 Isoform', Human mutation, vol. 37, no. 5, pp. 481-487. https://doi.org/10.1002/humu.22961

MYO3A Causes Human Dominant Deafness and Interacts with Protocadherin 15-CD2 Isoform. / Grati, M'hamed; Yan, Denise; Raval, Manmeet H.; Walsh, Tom; Ma, Qi; Chakchouk, Imen; Kannan-Sundhari, Abhiraami; Mittal, Rahul; Masmoudi, Saber; Blanton, Susan H.; Tekin, Mustafa; King, Mary Claire; Yengo, Christopher; Liu, Xue Zhong.

In: Human mutation, Vol. 37, No. 5, 01.05.2016, p. 481-487.

Research output: Contribution to journalArticle

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AU - Grati, M'hamed

AU - Yan, Denise

AU - Raval, Manmeet H.

AU - Walsh, Tom

AU - Ma, Qi

AU - Chakchouk, Imen

AU - Kannan-Sundhari, Abhiraami

AU - Mittal, Rahul

AU - Masmoudi, Saber

AU - Blanton, Susan H.

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Grati M, Yan D, Raval MH, Walsh T, Ma Q, Chakchouk I et al. MYO3A Causes Human Dominant Deafness and Interacts with Protocadherin 15-CD2 Isoform. Human mutation. 2016 May 1;37(5):481-487. https://doi.org/10.1002/humu.22961