|Year : 2021 | Volume
| Issue : 1 | Page : 14-21
Detection of two pathogenesis previously unreported myosin xva pathogenic variants in two large Iranian pedigrees with autosomal recessive nonsyndromic hearing loss
Fatemeh Azadegan-Dehkordi1, Korosh Ashrafi1, Gholam Reza Mobini2, Nasrin Yazdanpanahi3, Maryam Shirzad4, Effat Farrokhi1, Morteza Hashemzadeh-Chaleshtori1
1 Cellular and Molecular Research Center, Basic Health Sciences Institute, Shahrekord University of Medical Sciences, Isfahan, Iran
2 Medical Plants Research Center, Basic Health Sciences Institute, Shahrekord University of Medical Sciences, Isfahan, Iran
3 Department of Biochemistry, Falavarjan Branch, Islamic Azad University, Isfahan, Iran
4 Faculty of Paramedical Sciences, Shahrekord University of Medical Sciences, Shahrekord, Iran
|Date of Submission||26-Jun-2019|
|Date of Acceptance||13-Mar-2020|
|Date of Web Publication||26-Oct-2021|
Prof. Morteza Hashemzadeh-Chaleshtori
Cellular and Molecular Research Center, Basic Health Sciences Institute, Shahrekord University of Medical Sciences, Shahrekord
Source of Support: None, Conflict of Interest: None
Purpose: Hearing loss (HL) is a genetically heterogeneous common neurosensory disorder. Among different ethnic groups, pathogenic variants of Myosin XVa (MYO15A) at the DFNB3 locus are the common causes of autosomal recessive nonsyndromic hearing loss (ARNSHL). The aim of this study was to determine the prevalence and the type of MYO15A pathogenic variants in a subset of Iranian pedigrees with ARNSHL. Materials and Methods: Thirty-eight Iranian pedigrees with no Gap junction beta-2 pathogenic variants were included in the study. For all pedigrees, linkage analysis was performed using five short tandem repeat markers of DFNB3 locus. The DNA sequencing was then applied to identify MYO15A pathogenic variants in linked pedigrees. Results: Altogether, two out of 38 (5.3%) pedigrees were linked to locus 3. After sequencing, five previously unreported MYO15A pathogenic variants (c.1775-1776insA, c.1766-1767insC, c.7694delA, c.611G > C (G204A), and c.6442T > A (W2148R)) were revealed in homozygous and heterozygous state in the two pedigrees studied. Furthermore, the pathogenicity of pathogenic variants was confirmated by Insilco and cosegregation analysis in this study. Conclusions: Our findings support a relatively high prevalence and specificity of MYO15A pathogenic variant among Iranian ARNSHL patients. Molecular study of MYO15A may lead to elucidation of the population-specific pathogenic variant profile, which is of importance in molecular diagnostics of HL.
Keywords: Hearing loss, Myosin XVa, pathogenesis, previously unreported pathogenic variant, short tandem repeat
|How to cite this article:|
Azadegan-Dehkordi F, Ashrafi K, Mobini GR, Yazdanpanahi N, Shirzad M, Farrokhi E, Hashemzadeh-Chaleshtori M. Detection of two pathogenesis previously unreported myosin xva pathogenic variants in two large Iranian pedigrees with autosomal recessive nonsyndromic hearing loss. Indian J Otol 2021;27:14-21
|How to cite this URL:|
Azadegan-Dehkordi F, Ashrafi K, Mobini GR, Yazdanpanahi N, Shirzad M, Farrokhi E, Hashemzadeh-Chaleshtori M. Detection of two pathogenesis previously unreported myosin xva pathogenic variants in two large Iranian pedigrees with autosomal recessive nonsyndromic hearing loss. Indian J Otol [serial online] 2021 [cited 2021 Dec 2];27:14-21. Available from: https://www.indianjotol.org/text.asp?2021/27/1/14/329099
| Introduction|| |
Hearing loss (HL) is a common sensory impairment that affects >278 million in childhood-onset HL., Hereditary HL is genetically heterogeneous condition, exhibiting different patterns of inheritance that include: autosomal dominant, autosomal recessive, mitochondrial inheritance, X-linked, and Y-linked.,
Nonsyndromic HL represents 70% of all hereditary HL. Pathogenic variants account for approximately half of congenital or early-onset childhood HL that can have a broad range of severity., A majority of pathogenic variants in genes associated with recessive HL cause congenital or prelingual HL without associated clinical symptoms.
Autosomal dominant inheritance is typically associated with postlingual, progressive HL that can range from mild to profound at onset or over the course of many decades., Furthermore, 72 responsible loci and about 100 genes have been detected for nonsyndromic HL, of which 71 genes (hereditaryhearingloss.org) for autosomal recessive nonsyndromic hearing loss (ARNSHL) have been mapped., Pathogenic variants in these genes affect the cellular organization, cochlear homeostasis, cell growth, neuronal transmission, survival and differentiation, and tectorial membrane-associated proteins. The myosin, with 15 polypeptides and full-length Myosin XVa (MYO15A) is 3530 amino acid in length with an estimated molecular weight of 395 kDa and is encoded by MYO15A gene on human chromosome 17p11.2.
The human genome encodes different myosin proteins (almost 39 proteins) that are in 12 functional groups according to amino acid conservation in the motor domain. In humans, expression of wild-type myosin (3a, 6, 7a, 9, and 14) is necessary for normal hearing and loss of function of myosin 15 in the inner ear is not compensable., Myosins are actin-dependent motor molecules of a superfamily with ATPase activity. Furthermore, myosin's may be attached to membranous sections or can be bound to actin filaments and also relative in intracellular motility, and they contributed for the arrangement of stereocilia in mature hair bunches by divergent tails.,
Myosin-15 protein differs from other myosins in that it has a proline-rich 1233 residue N-terminal domain (133 kDa (that can be the conserved motor domain. Interestingly, variants in MYO15A are now identified as one of the common causes of severe to profound ARNSHL. The determination of MYO15A pathogenic variants in different ethnic populations can provide new insights into the genetic causes of HR, thus enabling better prognostication and better planning of management measures.
| Materials and Methods|| |
In this experimental study, 38 Iranian pedigrees with each pedigree having at least 3–7 loops were chosen. These families included 122 HL individuals with ARNSHL, which were selected from a total of more than 400 Iranian HL pedigrees by autosomal recessive syndromic, autosomal dominant, X-linked recessive, and mitochondrial hereditary patterns. Furthermore, there were no patients suspected to show syndromes in the 400 families with HL who were not involved in this study.
All pedigrees had a positive history of HL and were of Iranian ethnicity. The inclusion criteria were as follows:
- Autosomal recessive mode of inheritance should be suspected
- Clinical and demographic information should be provided
- There must be no syndromic (signs and symptoms other than deafness) or environmental evidence (infections such as rubella, meningitis, and ototoxic drugs). 4) At least two patients should exist in each of the pedigrees
- Families with no pathogenic variant in the Gap junction beta-2 (GJB2) gene.
In addition, a written consent form had been provided for all the patients in our previous study. After filling out an informed consent form by subjects or their parents (children under the age of 18 years), about 5 ml of peripheral blood from all the ARNSHL pedigrees members were collected in tubes containing ethylenediamine tetraacetic acid (0.5 M).
Based on the interviews with the adult members of these pedigrees, informational questionnaires had to be filled out, and pedigrees were drawn. This study was approved by the Institutional Review Boards of the Shahrekord University of Medical Sciences, Shahrekord, Iran, in 2016 (Grant No. 2165). Two consanguineous Iranian pedigrees (pedigrees IR-23, and IR-51), with two and three HL patients, respectively, were linked to the DFNB3 locus for further study.
For each patient (6–40 years old), a complete medical history was explored to record the age of HL onset and to ensure that HL was not the result of environmental factors including maternal-to-fetal infections, perinatal complications, bacterial or viral infection (meningitis), prenatal and postnatal ototoxic drugs such as aminoglycosides.
In general, a complete clinical evaluation was done, including audiological examination, physical examinations, and ophthalmologic evaluation for vision problems in all pedegrees. They were also tested for proteinuria and hematuria. These examinations were performed with no other obvious deficits detected. HL in this study was not due to Pendred syndrome, Usher syndrome type 1 or 2, Waardenburg syndrome type 1 or 2 or any other reported syndromal form of HL.
Clinical and physical examination
For all cases, pure-tone audiometric test average for air and bone conduction at frequencies of 500,1000, 2000, and 4000 Hz was performed to clarify HL severity as follows: mild: 21–45 dB; moderate: 46–60 dB; moderately severe: 61–75 dB; severe: 76–96 dB; and profound: ≥97 dB. Furthermore, HL severity of all patients with conventional auditory brainstem response testing was performed by certified audiologists (which are not shown in this study).
Radiological examination of temporal bone
For all patients of the linked pedigrees, temporal bone computed tomography scan was conducted using Somatom Sensation Emotion 16-Slice Configuration (Siemens Medical Solutions, Erlangen, Germany) to clarify the vestibular aqueduct situation. According to this experiment, enlarged vestibular aqueduct (EVA) in patients was not observed.
For assessing the thyroid phenotype in all the patients in the two pedigrees, thyroid-stimulated hormone, thyroxin (T4), and triiodothyronine (T3) levels were measured using a chemiluminescent immunoassay (Berthold Technology-CSA, Germany). Furthermore, ultrasonography was performed with a Sonoline G50 Ultrasound System (Siemens Medical Solutions, Erlangen, Germany) to determine the thyroid size in all patients. Thyroid ultrasonography and hormone investigation results were interpreted according to the sex and age of the patients and these results were normal in all of the patients in the two pedigrees.
DNA was extracted using a DNA extraction kit (DNPTM, CinnaGen, Tehran, Iran). DNA concentration and absorbance ratios were tested with Nanodrop spectrophotometer (Thermo Scientific NanoDrop 1000 Spectrophotometer, Thermo Scientific, Wilmington, USA).
Genetic analysis of gap junction beta-2 and myosin XVa
Using sequence analysis, the 50 pedigrees were examined for pathogenic variants in their GJB2 gene. Thirty-eight pedigrees with no pathogenic variant of GJB2 (38 out of 50 Iranian deaf pedigrees), according to the previous study (submitted), were screened by genotyping the short tandem repeat (STR) markers [Table 1]. Linkage analysis followed by sequencing of MYO15A gene for 2 linked pedigrees.
|Table 1: The short tandem repeat markers of DFNB3 (MYO15A) (18, 108, 706-18, 179, 802) and their primer sequences|
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Amplification of the short tandem repeat markers and linkage analysis
SLINK was estimated by the pedigrees option of EasyLinkage (version 5.05 (Medical University Clinic at the University of Würzburg, Würzburg, Germany)) to evaluate power of the 38 pedigrees for linkage strategy. STR markers and primers were selected based on NCBI Map Viewer and Uni STS data. Logarithm of the odds (LOD) scores of two-point and multi-point were calculated using SuperLink (version 1.6) and GeneHunter (version 2.91 (Berlin-Buch, Germany)). For LOD calculation, complete penetrance, autosomal recessive inheritance, disease-allele frequency of 0.001, no phenocopy, equal recombination frequencies in both males and females were assumed [Table 2]. Furthermore, reconstruction of haplotypes was done by HaploPainter software (version 029. 5 (Berlin-Buch, Germany)) [Figure 1]. Polymerase chain reaction (PCR) was applied for the amplification of five DFNB3 STR markers. The amplified conditions were as follows: reaction volume was 15 μl with a final concentration of ddH2O 7.5 μl, master mi × 5.5 μl, forward primer (20 pmol/μl) 0.5 μl, reverse primer (20 pmol/μl) 0.5 μl, and template genomic DNA (100 ng/μl) 1 μl. The thermal cycle profile for PCR (Program Temp Control System PC-700, ASTEC, Fukuoka, Japan) was as follows: 95°C for 1 min, 30–35 cycles: 95°C for 1 min, annealing temperature for 24 s for different markers (51°C–59°C), 72°C for 35 s, and finally, 72°C for 8 min. PCR amplicons were analyzed on a 15% polyacrylamide gel electrophoresis (PAGE) [Figure 1].
|Table 2: Maximum S-Link and logarithm of the odds scores for two families linked to DFNB3|
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|Figure 1: Haplotype analysis in the IR-23 pedigree was shown in up figure and being linked to the D17S921 marker of Myosin XVa gene was detected by the 15% polyacrylamide gel at this pedigree in the down figure. Healthy individuals were heterozygous (1/2); all patients were homozygous (2/2) and results of the cosegregation analysis of the IF-23 family|
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Pathogenic variant analysis of myosin XVa gene by sequencing analysis
All affected individuals of IR-23, and IR-51 pedigrees who were linked to DFNB3, were subjected to sequencing of all 66 exons and exon–intron boundaries of MYO15A. PCR amplification was conducted by primers designed by Oligo software (version 5.1; National Biosciences, Inc., Plymouth, Minn., USA). The amplification conditions were as follows: reaction volume was 15 μl with a final concentration of 7.5 μl, master mi × 5.5 μl, forward primer (20 pmol/μl) 0.5 μl, reverse primer (20 pmol/μl) 0.5 μl, and template genomic DNA 1 μl (100 ng/μl). The thermal cycle profile for PCR (Program Temp Control System PC-700, ASTEC, Fukuoka, Japan) was as follows: initial denaturation step of 5 min at 95°C, followed by 32–33 cycles of 30 s at 95°C, annealing of 30-s for different primers at 54°C–63°C, and a 24-s extension at 72°C, with a final extension for 5 min at 72°C. The sequencing was carried out in SEQLAB (Sequence Laboratories, Gottingen, Germany) [Figure 2]. The variants observed in this study were investigated by the Insilco analysis to find out the type of change and the effects of these variables on DNA and its products as well as pathogenicity and conservation.
|Figure 2: Electropherograms from the normal (a), c.1766_1767insC homozygous (b), normal (c) and c.1775_1776insA homozygous in patients (d) and c.1775_1776insA heterozygous in health parents (e) and normal (f) c.7694delA homozygous in patients (g) and c.7694delA heterozygous in health parents (h) genotypes are shown. Arrows show the location of the base change|
Click here to view
| Results|| |
The 66 exons and exon–intron boundaries of MYO15A were analyzed by direct DNA sequencing from all individuals of IR-23 and IR-51 pedigrees, and these two pedigrees were linked to DFNB3 locus. All the patients with the pathogenic variant had profound HL. In IR-23 pedigree two previously unreported homozygous pathogenic variants; c.1775_1776insA and c. 1766_1767insC were detected. In the IR-51 family, one previously unreported homozygous pathogenic variant; c.7694delA was detected. In this study pedigree IR-51 was also detected with c. 611G > C previously unreported heterozygous pathogenic variant in exon 2 and in family IR-23, c.6442T > A previously unreported heterozygous pathogenic variant in exon 30 was detected [Table 3] that these two heterozygous pathogenic variants were pathogenesis according to In silco [Table 4].
In addition, in these two families, a total of 9 other homozygous sequence variants were found. Four of these variants are previously unreported and five of them are already known, also among the 10 other heterozygous sequence variants detected seven variants were previously unreported and three were known [Table 5], meanwhile, based on reviews by pathogenic variant taster site (http://pathogenic varianttaster.org) except for two new pathogens pathogenic variants, the other 17 variants are single-nucleotide polymorphisms [Figure 3].
|Figure 3: MYO15A gene structure, with previously unreported pathogenic variants reported in this study indicated at the top of the figure and previously reported polymorphisms (*) and previously unreported polymorphisms listed at the bottom of the figure|
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Results of the cosegregation analysis of the IF23 family
After analyzing the results of the sequencing of the 2 exon of the MYO15 A gene, c.1775_1776insA pathogenic variant was showed cosegregation. Hence that all healthy family members, including parents, were heterozygote for two c.1775_1776insA pathogenic variant, and all patients were homozygous for this pathogenic variant [Figure 1]. In this way, the results of the cosegregation analysis and Insilco [Table 4] were in favor of the pathogenesis of this pathogenic variant.
Results of the cosegregation analysis of the IF51 family
After analyzed the results of the sequencing of the 40 exon of the MYO15A gene, the c. 7694delA pathogenic variant was also showed cosegregation. So that all healthy family members, including parents, had a heterozygote state for c. 7694delA pathogenic variant and all patients were homozygous for this pathogenic variant [Figure 4]. In this way, the results of the cosegregation analysis and In silco [Table 4] were in favor of the pathogenicity of this new pathogenic variant.
Clinical characterizations of families with MYO15A pathogenic variants have been reviewed. All the patients with the pathogenic variant had profound: ≥97 dB HL. Pendred syndrome (EVA) and another syndrome were not seen in any of the pedigrees tested. None of the pedigrees with pathogenic variants showed goiter. Phenotype of the thyroid was normal among the patients.
| Discussion|| |
In this research, 38 families segregating congenital profound HL were studied. These patients showed no response to pure-tone audiology [Figure 5]. Furthermore in the previous study, 38 families who did not possess pathogenic variant in GJB2 gene were isolated.
Based on the presence of profound HL, linkage analysis for DFNB3 locus was prioritized and linkage to the locus was found in two families. Hence, DNA sequencing of the MYO15A gene, led to the detection of 5 previously unreported pathogenic variants, suggesting a frequency of the previously unreported homozygous pathogenic variants in MYO15A which was 2 out of the 38 (5.3%) pedigrees and the frequency of previously unreported heterozygous pathogenic pathogenic variants in the MYO15A was also 2 out of the 38 (5.3%) pedigrees in Iranian patients with congenital profound HL. All the patients of IR-23 family were homozygous for c.1775_1776insA pathogenesis previously unreported pathogenic variant and they were heterozygous for c.6442T > A pathogenesis previously unreported pathogenic variant and had profound HL; also all the patients of IR-51 family had homozygous c.7694delA pathogenesis previously unreported pathogenic variant and c. 611G >C pathogenesis previously unreported heterozygous pathogenic variant, showed profound HL.
The c.1775_1776insA and c.1766_1767insC previously unreported pathogenic variants in exon 2 of this gene and N-terminal peptide extension of the protein could cause a complete loss of function of MYO15A or shorter protein with defective function which leads us to conclude that this degree of HL (profound) is the common one in MYO15A-related recessive HL, but according to cosegregation analysis and In silco. The c.1775_1776insA homozygous pathogenic variant was pathogenesis in this pedigree, and in this study c.1766_1767insC previously unreported pathogenic variant not pathogenic. In the present investigation, the c.7694delA C-terminal peptide extension of the protein would result in the production of a shorter protein with defective function.
This study showed that MYO15A pathogenic variants are a relatively frequent cause of HL in the cohort, which is genetically highly heterogeneous. The DFNB3 locus for ARNSHL was first identified by linkage analysis in 48 HL individuals who were approximately from the entire population of Bengkala, and in the other study, the frequency of DFNB3 pathogenic variants in Indonesia reported about 9.4% in 2185 cases and then was further refined to chromosome 17p11.2. There is a relatively high pathogenic variant frequency of MYO15A-related HL in the neighboring countries of Iran (Pakistan 5% in 7 families and Turkey 9.9% in 104 families)., Furthermore, in Iran 5.71% in 140 families, and in another study, 302 Iranian families with MYO15A pathogenic variants frequency accounted for 9.6% of the HL.
To date <86 pathogenic variants of the MYO15A gene have been detected in HL populations, and most of these pathogenic variants cause autosomal recessive nonsyndromic congenital profound HL. The MYO15A gene with 66 exons encodes had several alternatively spliced transcripts in the inner ear. The full-length transcript has 3530 amino acids, including a long N-terminal extension (coded by exon 2), a motorhead domain, the neck region has two light chain-binding motifs (IQ), and the long tail region has two myosin tail homology 4 domains, two-band 4.1 F-ezrin-radixin-moesin domains, a putative Src-homology-3 domain and a C-terminal class I PDZ binding domain., MYO15A protein is mainly expressed in the cuticular plate and stereocilia of the cochlear inner and outer hair cells and is commonly localized at the tips of stereocilia of the inner ear. MYO15A is involved in vestibular hair cells. Multiple alignment of human Myosin-XV protein by SIFT (http://sift.jcvi.org), and ConSeq (http://conseq.tau.ac.il/).software showed a high level of conservation for the location of these pathogenic variants among different kinds of species.Since these two variants are in the exons, result in frameshift followed by an early stop codon, which generally changes the sequence of the amino acids from the location of the pathogenic variant to the next so that it will alter the length and sequence of the RNA and the protein. It will also lead to loss or gain of the main part of the functional protein. These effects will increase the chance of pathogenicity of these pathogenic variants. Due to the high level of conservation of these amino acids, it seems that these amino acids may have an important role in the MYO15 protein, and pathogenic variants at these sites can play a role in the pathogenesis of HL.
In c. 611G >C pathogenic variant, the glycine at position 204 is substituted by alanine. Both of these amino acids are neutral– polar and highly conserved [Table 3]. In c. 6442T >A pathogenic variant, tryptophan (a nonpolar amino acid) at position 2148 is substituted by arginine that is a highly conserved and polar amino acid with a positive charge. Accordingly, these variations are in exons and highly conserved; therefore, it is possible for the substitutions to alter the structure and function of the protein and this may enhance the pathogenicity. The cause of the HL in the remaining families does not detect to be related to pathogenic variants in MYO15A and other unidentified loci may be involved, although environmental factors could not be fully related to HL.
Furthermore, the structure of MYO15A protein is still challenging and has not been exactly identified. Studies of the effects of previously unreported MYO15A pathogenic variants on MYO15A protein can provide additional beneficial information about the relation between the structural function of this protein; however, other structural features can also be depicted.
| Conclusions|| |
Two homozygous variants in the MYO15A gene were the pathogenic variants in two ARNSHL pedigrees, according to the cosegregation analysis and checking servers determined the pathogenesis of the nucleotide changes. Our investigation detected that ARNSHL is an extremely heterogeneous genetic disorder. Our findings confirm the high frequency of MYO15A pathogenic variants in Iran and have implications in genetic counseling for the ARNSHL families. The result of this study revealed an MYO15A pathogenic variantal frequency of 5.3% in our cohort of Iranian HL individuals. Sequencing of the MYO15A gene led to the detection of 5 previously unreported pathogenic variants, including 3 deletion and insertion pathogenic variants as well as two missense pathogenic variants in different exons of the MYO15A gene.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
Korosh Ashrafi and Fatemeh Azadegan-Dehkordi contributed equally in preparation of this paper. All authors contributed in preparation of the first draft and confirmed the last version. Morteza Hashemzadeh-Chaleshtori edited the last version.
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[Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5]
[Table 1], [Table 2], [Table 3], [Table 4], [Table 5]