A novel missense mutation in SMPX causes a rare form of X-linked postlingual sensorineural hearing loss in a Chinese family

Guo, Yingyuan; Yu, Hao; Zhang, Dejun; Xu, Hongen; Yu, Duo‐Jiao; Lv, Jingmao; Fu, Zhongying; Han, Shuang; Guo, Fang; Bai, Jie; Guan, Guofang

doi:10.21037/tp-20-435

Cited by 3 publications

(6 citation statements)

References 26 publications

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“…In summary, our work provides the functional evidence that strongly supports previous data connecting SMPX mutations and hearing loss in humans [ 1 , 2 , 3 , 18 , 19 , 20 , 21 , 22 , 23 , 24 , 25 ]. Indeed, smpx downregulation in zebrafish embryos resulted in profound structural and functional alterations of the larval inner ear, also raising the possibility that SMPX -linked hearing loss might represent a developmental defect, as suggested by some cases of pre-lingual hearing loss [ 23 ] and not just the result of the lack of a protein involved in preserving the hair cells from mechanical stress [ 43 ].…”

Section: Discussionsupporting

confidence: 90%

“…Historically, SMPX has always been considered to be an NSHL gene because in human patients no other relevant symptoms have been associated with its mutations [ 1 , 2 , 3 , 18 , 19 , 20 , 21 , 22 , 23 , 24 , 25 ]. Surprisingly, we observed a previously unreported disease phenotype concerning skeletal muscle.…”

Section: Discussionmentioning

confidence: 99%

“…Mutations in SMPX represent the genetic origin to explain several cases of X-linked congenital deafness and progressive NSHL in humans [ 1 , 2 , 3 , 18 , 19 , 20 , 21 , 22 , 23 , 24 , 25 ]. All of the pathogenic forms of SMPX are associated with the transcription and maturation of aberrant mRNAs that face degradation through the nonsense-mediated mRNA decay process.…”

Section: Introductionmentioning

confidence: 99%

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Inner Ear and Muscle Developmental Defects in Smpx-Deficient Zebrafish Embryos

Ghilardi

Diana

Bacchetta

et al. 2021

IJMS

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The last decade has witnessed the identification of several families affected by hereditary non-syndromic hearing loss (NSHL) caused by mutations in the SMPX gene and the loss of function has been suggested as the underlying mechanism. In the attempt to confirm this hypothesis we generated an Smpx-deficient zebrafish model, pointing out its crucial role in proper inner ear development. Indeed, a marked decrease in the number of kinocilia together with structural alterations of the stereocilia and the kinocilium itself in the hair cells of the inner ear were observed. We also report the impairment of the mechanotransduction by the hair cells, making SMPX a potential key player in the construction of the machinery necessary for sound detection. This wealth of evidence provides the first possible explanation for hearing loss in SMPX-mutated patients. Additionally, we observed a clear muscular phenotype consisting of the defective organization and functioning of muscle fibers, strongly suggesting a potential role for the protein in the development of muscle fibers. This piece of evidence highlights the need for more in-depth analyses in search for possible correlations between SMPX mutations and muscular disorders in humans, thus potentially turning this non-syndromic hearing loss-associated gene into the genetic cause of dysfunctions characterized by more than one symptom, making SMPX a novel syndromic gene.

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Section: Discussionsupporting

confidence: 90%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Inner Ear and Muscle Developmental Defects in Smpx-Deficient Zebrafish Embryos

Ghilardi

Diana

Bacchetta

et al. 2021

IJMS

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“…In our families, in contrast, affected adult males examined in their 6th–8th decades showed no hearing loss and neither reported any hearing impairment in their relatives. Interestingly, the first SMPX missense mutation causing hearing loss was recently described [ 10 ]. Replacing the C-terminal glutamine residue of SMPX with glutamate, this mutation creates a C-degron motif EE that is predicted to destabilize the protein [ 17 ], likely resulting in a hypomorphic allele pathomechanistically similar to the other hearing-loss mutations.…”

Section: Discussionmentioning

confidence: 99%

Missense mutations in small muscle protein X-linked (SMPX) cause distal myopathy with protein inclusions

et al. 2021

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Using deep phenotyping and high-throughput sequencing, we have identified a novel type of distal myopathy caused by mutations in the Small muscle protein X-linked (SMPX) gene. Four different missense mutations were identified in ten patients from nine families in five different countries, suggesting that this disease could be prevalent in other populations as well. Haplotype analysis of patients with similar ancestry revealed two different founder mutations in Southern Europe and France, indicating that the prevalence in these populations may be higher. In our study all patients presented with highly similar clinical features: adult-onset, usually distal more than proximal limb muscle weakness, slowly progressing over decades with preserved walking. Lower limb muscle imaging showed a characteristic pattern of muscle involvement and fatty degeneration. Histopathological and electron microscopic analysis of patient muscle biopsies revealed myopathic findings with rimmed vacuoles and the presence of sarcoplasmic inclusions, some with amyloid-like characteristics. In silico predictions and subsequent cell culture studies showed that the missense mutations increase aggregation propensity of the SMPX protein. In cell culture studies, overexpressed SMPX localized to stress granules and slowed down their clearance.

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“…In the last decade, mutations in the SMPX gene have been associated with nonsyndromic X-linked hearing loss DFNX4 4 – 14 . Interestingly, SMPX was shown to be abundantly expressed in both fetal and adult human inner ear 4 , while mouse Smpx was concordantly expressed with the master regulator of inner ear hair cell (HC) specification, the transcription factor Atoh1, in all vestibular organs and all cochlear turns of the developing mouse inner ear, thus suggesting a Smpx putative role during HC differentiation and/or functioning 15 .…”

Section: Introductionmentioning

confidence: 99%

Differentiation and functioning of the lateral line organ in zebrafish require Smpx activity

Diana,

Ghilardi,

Del Giacco

2024

Sci Rep

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The small muscle protein, X-linked (SMPX) gene encodes a cytoskeleton-associated protein, highly expressed in the inner ear hair cells (HCs), possibly regulating auditory function. In the last decade, several mutations in SMPX have been associated with X-chromosomal progressive non syndromic hearing loss in humans and, in line with this, Smpx-deficient animal models, namely zebrafish and mouse, showed significant impairment of inner ear HCs development, maintenance, and functioning. In this work, we uncovered smpx expression in the neuromast mechanosensory HCs of both Anterior and Posterior Lateral Line (ALL and PLL, respectively) of zebrafish larvae and focused our attention on the PLL. Smpx was subcellularly localized throughout the cytoplasm of the HCs, as well as in their primary cilium. Loss-of-function experiments, via both morpholino-mediated gene knockdown and CRISPR/Cas9 F0 gene knockout, revealed that the lack of Smpx led to fewer properly differentiated and functional neuromasts, as well as to a smaller PLL primordium (PLLp), the latter also Smpx-positive. In addition, the kinocilia of Smpx-deficient neuromast HCs appeared structurally and numerically altered. Such phenotypes were associated with a significant reduction in the mechanotransduction activity of the neuromast HCs, in line with their positivity for Smpx. In summary, this work highlights the importance of Smpx in lateral line development and, specifically, in proper HCs differentiation and/or maintenance, and in the mechanotransduction process carried out by the neuromast HCs. Because lateral line HCs are both functionally and structurally analogous to the cochlear HCs, the neuromasts might represent an invaluable—and easily accessible—tool to dissect the role of Smpx in HCs development/functioning and shed light on the underlying mechanisms involved in hearing loss.

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A novel missense mutation in SMPX causes a rare form of X-linked postlingual sensorineural hearing loss in a Chinese family

Cited by 3 publications

References 26 publications

Inner Ear and Muscle Developmental Defects in Smpx-Deficient Zebrafish Embryos

Inner Ear and Muscle Developmental Defects in Smpx-Deficient Zebrafish Embryos

Missense mutations in small muscle protein X-linked (SMPX) cause distal myopathy with protein inclusions

Differentiation and functioning of the lateral line organ in zebrafish require Smpx activity

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