Analysis of the Mutational Landscape of Osteosarcomas Identifies Genes Related to Metastasis and Prognosis and Disrupted Biological Pathways of Immune Response and Bone Development.

Osteosarcoma (OS) is the most prevalent type of bone tumor, but slow progress has been achieved in disentangling the full set of genomic events involved in its initiation and progression. We assessed by NGS the mutational spectrum of 28 primary OSs from Brazilian patients, and identified 445 potentially deleterious SNVs/indels and 1176 copy number alterations (CNAs). TP53 was the most recurrently mutated gene, with an overall rate of ~60%, considering SNVs/indels and CNAs. The most frequent CNAs (~60%) were gains at 1q21.2q21.3, 6p21.1, and 8q13.3q24.22, and losses at 10q26 and 13q14.3q21.1. Seven cases presented CNA patterns reminiscent of complex events (chromothripsis and chromoanasynthesis). Putative RB1 and TP53 germline variants were found in five samples associated with metastasis at diagnosis along with complex genomic patterns of CNAs. PTPRQ, KNL1, ZFHX4, and DMD alterations were prevalent in metastatic or deceased patients, being potentially indicative of poor prognosis. TNFRSF11B, involved in skeletal system development and maintenance, emerged as a candidate for osteosarcomagenesis due to its biological function and a high frequency of copy number gains. A protein-protein network enrichment highlighted biological pathways involved in immunity and bone development. Our findings reinforced the high genomic OS instability and heterogeneity, and led to the identification of novel disrupted genes deserving further evaluation as biomarkers due to their association with poor outcomes.

PNPT1, MYO15A, PTPRQ, and SLC12A2-associated genetic and phenotypic heterogeneity among hearing impaired assortative mating families in Southern India.

The study was conducted between 2018 and 2020. From a cohort of 113 hearing impaired (HI), five non-DFNB12 probands identified with heterozygous CDH23 variants were subjected to exome analysis. This resolved the etiology of hearing loss (HL) in four South Indian assortative mating families. Six variants, including three novel ones, were identified in four genes: PNPT1 p.(Ala46Gly) and p.(Asn540Ser), MYO15A p.(Leu1485Pro) and p.(Tyr1891Ter), PTPRQ p.(Gln1336Ter), and SLC12A2 p.(Pro988Ser). Compound heterozygous PNPT1 variants were associated with DFNB70 causing prelingual profound sensorineural hearing loss (SNHL), vestibular dysfunction, and unilateral progressive vision loss in one family. In the second family, MYO15A variants in the myosin motor domain, including a novel variant, causing DFNB3, were found to be associated with prelingual profound SNHL. A novel PTPRQ variant was associated with postlingual progressive sensorineural/mixed HL and vestibular dysfunction in the third family with DFNB84A. In the fourth family, the SLC12A2 novel variant was found to segregate with severe-to-profound HL causing DFNA78, across three generations. Our results suggest a high level of allelic, genotypic, and phenotypic heterogeneity of HL in these families. This study is the first to report the association of PNPT1, PTPRQ, and SLC12A2 variants with HL in the Indian population.

First confirmatory study on PTPRQ as an autosomal dominant non-syndromic hearing loss gene.

BACKGROUND: Biallelic PTPRQ pathogenic variants have been previously reported as causative for autosomal recessive non-syndromic hearing loss. In 2018 the first heterozygous PTPRQ variant has been implicated in the development of autosomal dominant non-syndromic hearing loss (ADNSHL) in a German family. The study presented the only, so far known, PTPRQ pathogenic variant (c.6881G>A) in ADNSHL. It is located in the last PTPRQ coding exon and introduces a premature stop codon (p.Trp2294*). METHODS: A five-generation Polish family with ADNSHL was recruited for the study (n = 14). Thorough audiological, neurotological and imaging studies were carried out to precisely define the phenotype. Genomic DNA was isolated from peripheral blood samples or buccal swabs of available family members. Clinical exome sequencing was conducted for the proband. Family segregation analysis of the identified variants was performed using Sanger sequencing. Single nucleotide polymorphism array on DNA samples from the Polish and the original German family was used for genome-wide linkage analysis. RESULTS: Combining clinical exome sequencing and family segregation analysis, we have identified the same (NM_001145026.2:c.6881G>A, NP_001138498.1:p.Trp2294*) PTPRQ alteration in the Polish ADNSHL family. Using genome-wide linkage analysis, we found that the studied family and the original German family derive from a common ancestor. Deep phenotyping of the affected individuals showed that in contrast to the recessive form, the PTPRQ-related ADNSHL is not associated with vestibular dysfunction. In both families ADNSHL was progressive, affected mainly high frequencies and had a variable age of onset. CONCLUSION: Our data provide the first confirmation of PTPRQ involvement in ADNSHL. The finding strongly reinforces the inclusion of PTPRQ to the small set of genes leading to both autosomal recessive and dominant hearing loss.

Novel PTPRQ mutations identified in three congenital hearing loss patients with various types of hearing loss.

OBJECTIVES: We present 3 patients with congenital sensorineural hearing loss (SNHL) caused by novel PTPRQ mutations, including clinical manifestations and phenotypic features. METHODS: Two hundred twenty (220) Japanese subjects with SNHL from unrelated and nonconsanguineous families were enrolled in the study. Targeted genomic enrichment with massively parallel DNA sequencing of all known nonsyndromic hearing loss genes was performed to identify the genetic cause of hearing loss. RESULTS: Four novel causative PTPRQ mutations were identified in 3 cases. Case 1 had progressive profound SNHL with a homozygous nonsense mutation. Case 2 had nonprogressive profound SNHL with a compound heterozygous mutation (nonsense and missense mutation). Case 3 had nonprogressive moderate SNHL with a compound heterozygous mutation (missense and splice site mutation). Caloric test and vestibular evoked myogenic potential (VEMP) test showed vestibular dysfunction in Case 1. CONCLUSION: Hearing loss levels and progression among the present cases were varied, and there seem to be no obvious correlations between genotypes and the phenotypic features of their hearing loss. The PTPRQ mutations appeared to be responsible for vestibular dysfunction.

Novel PTPRQ variants associated with hearing loss in a Chinese family PTPRQ variants in Chinese hearing loss.

Introduction: Hearing loss is one of the most prevalent congenital sensory disorders. Over 50% of congenital hearing loss cases are attributed to genetic factors. The PTPRQ gene encodes the protein tyrosine phosphatase receptor Q, which plays an important role in maintaining the structure and function of the stereocilia of hair cells. Variants in the PTPRQ gene have been implicated in hereditary sensorineural hearing loss. Methods and Results: Utilizing next-generation sequencing technology, we identified novel compound heterozygous variants (c.977G>A:p.W326X and c.6742C>T:p.Q2248X) in the PTPRQ gene within a Chinese national lineage, marking the first association of these variants with hereditary sensorineural hearing loss. Discussion: Our findings further emphasize the critical role of PTPRQ in auditory function and contribute to a more comprehensive understanding of PTPRQ-associated hearing loss mechanisms, aiding in clinical management and genetic counseling.

Detailed Clinical Features of PTPRQ-Associated Hearing Loss Identified in a Large Japanese Hearing Loss Cohort.

The PTPRQ gene has been identified as one of the genes responsible for non-syndromic sensorineural hearing loss (SNHL), and assigned as DFNA73 and DFNB84. To date, about 30 causative PTPRQ variants have been reported to cause SNHL. However, the detailed clinical features of PTPRQ-associated hearing loss (HL) remain unclear. In this study, 15,684 patients with SNHL were enrolled and genetic analysis was performed using massively parallel DNA sequencing (MPS) for 63 target deafness genes. We identified 17 possibly disease-causing PTPRQ variants in 13 Japanese patients, with 15 of the 17 variants regarded as novel. The majority of variants identified in this study were loss of function. Patients with PTPRQ-associated HL mostly showed congenital or childhood onset. Their hearing levels at high frequency deteriorated earlier than that at low frequency. The severity of HL progressed from moderate to severe or profound HL. Five patients with profound or severe HL received cochlear implantation, and the postoperative sound field threshold levels and discrimination scores were favorable. These findings will contribute to a greater understanding of the clinical features of PTPRQ-associated HL and may be relevant in clinical practice.

Novel FERMT3 and PTPRQ Mutations Associated with Leukocyte Adhesion Deficiency-III and Sensorineural Hearing Loss.

Leukocyte adhesion deficiency-III (LAD-III) is a rare genetic disease caused by defective integrin activation in hematopoietic cells due to mutations in the FERMT3 gene. The PTPRQ gene encodes the protein tyrosine phosphatase receptor Q and is essential for the normal maturation and function of hair bundle in the cochlea. Homozygous PTPRQ mutations impair the stereocilia in hair cells which lead to nonsyndromic sensorineural hearing loss (SNHL) with vestibular dysfunction. Here, we report two novel pathogenic homozygous mutations found in two genes, FERMT3 and PTPRQ , in a Brazilian patient with LAD-III and SNHL, which may develop our understanding of the phenotype-genotype correlation and prognosis of patients with these rare diseases.

Protein Tyrosine Phosphatase Receptor-type Q: Structure, Activity, and Implications in Human Disease.

Protein tyrosine phosphatase receptor-type Q (PTPRQ), a member of the type III tyrosine phosphatase receptor (R3 PTPR) family, is composed of three domains, including 18 extracellular fibronectin type III (FN3) repeats, a transmembrane helix, and a cytoplasmic phosphotyrosine phosphatase (PTP) domain. PTPRQ was initially identified as a transcript upregulated in glomerular mesangial cells in a rat model of glomerulonephritis. Subsequently, studies found that PTPRQ has phosphotyrosine phosphatase and phosphatidylinositol phosphatase activities and can regulate cell proliferation, apoptosis, differentiation, and survival. Further in vivo studies showed that PTPRQ is necessary for the maturation of cochlear hair bundles and is considered a potential gene for deafness. In the recent two decades, 21 mutations in PTPRQ have been linked to autosomal recessive hearing loss (DFNB84) and autosomal dominant hearing loss (DFNA73). Recent mutations, deletions, and amplifications of PTPRQ have been observed in many types of cancers, which indicate that PTPRQ might play an essential role in the development of many cancers. In this review, we briefly describe PTPRQ structure and enzyme activity and focus on the correlation between PTPRQ and human disease. A profound understanding of PTPRQ could be helpful in the identification of new therapeutic targets to treat associated diseases.

Targeted Next-Generation Sequencing Identified Novel Compound Heterozygous Variants in the PTPRQ Gene Causing Autosomal Recessive Hearing Loss in a Chinese Family.

Hearing loss is among the most common congenital sensory impairments. Genetic causes account for more than 50% of the cases of congenital hearing loss. The PTPRQ gene, encoding protein tyrosine phosphatase receptor Q, plays an important role in maintaining the stereocilia structure and function of hair cells. Mutations in the PTPRQ gene have been reported to cause hereditary sensorineural hearing loss. By using next-generation sequencing and Sanger sequencing, we identified a novel compound heterozygous mutation (c.997 G > A and c.6603-3 T > G) of the PTPRQ gene in a Chinese consanguineous family. This is the first report linking these two mutations to recessive hereditary sensorineural hearing loss. These findings contribute to the understanding of the relationship between genotype and hearing phenotype of PTPRQ-related hearing loss, which may be helpful to clinical management and genetic counseling.

Whole-exome sequencing identified a novel heterozygous mutation of SALL1 and a new homozygous mutation of PTPRQ in a Chinese family with Townes-Brocks syndrome and hearing loss.

BACKGROUND: Previous studies have revealed that mutations of Spalt Like Transcription Factor 1 (SALL1) are responsible for Townes-Brocks syndrome (TBS), a rare genetic disorder that is characterized by an imperforate anus, dysplastic ears, thumb malformations and other abnormalities, such as hearing loss, foot malformations, renal impairment with or without renal malformations, genitourinary malformations, and congenital heart disease. In addition, the protein tyrosine phosphatase receptor type Q (PTPRQ) gene has been identified in nonsyndromic hearing loss patients with autosomal recessive or autosomal dominant inherited patterns. METHODS: A Chinese family with TBS and hearing loss was enrolled in this study. The proband was a two-month-old girl who suffered from congenital anal atresia with rectal perineal fistula, ventricular septal defect, patent ductus arteriosus, pulmonary hypertension (PH), and finger deformities. The proband's father also had external ear deformity with deafness, toe deformities and PH, although his anus was normal. Further investigation found that the proband's mother presented nonsyndromic hearing loss, and the proband's mother's parents were consanguine married. Whole-exome sequencing and Sanger sequencing were applied to detect the genetic lesions of TBS and nonsyndromic hearing loss. RESULTS: Via whole-exome sequencing and Sanger sequencing of the proband and her mother, we identified a novel heterozygous mutation (ENST00000251020: c.1428_1429insT, p. K478QfsX38) of SALL1 in the proband and her father who presented TBS phenotypes, and we also detected a new homozygous mutation [ENST00000266688: c.1057_1057delC, p. L353SfsX8)] of PTPRQ in the proband's mother and uncle, who suffered from nonsyndromic hearing loss. Both mutations were located in the conserved sites of the respective protein and were predicted to be deleterious by informatics analysis. CONCLUSIONS: This study confirmed the diagnosis of TBS at the molecular level and expanded the spectrum of SALL1 mutations and PTPRQ mutations. Our study may contribute to the clinical management and genetic counselling of TBS and hearing loss.

Deafness and vestibular dysfunction in a Doberman Pinscher puppy associated with a mutation in the PTPRQ gene.

BACKGROUND: A congenital syndrome of hearing loss and vestibular dysfunction affects Doberman Pinschers. Its inheritance pattern is suspected to be autosomal recessive and it potentially represents a spontaneous animal model of an autosomal recessive syndromic hearing loss. HYPOTHESIS/OBJECTIVES: The objectives of this study were to use whole genome sequencing (WGS) to identify deleterious genetic variants in candidate genes associated with the syndrome and to study the prevalence of candidate variants among a population of unaffected Doberman Pinschers. ANIMALS: One affected Doberman Pinscher and 202 unaffected Doberman Pinschers. METHODS: WGS of the affected dog with filtering of variants against a database of 154 unaffected dogs of diverse breeds was performed. Confirmation of candidate variants was achieved by Sanger sequencing followed by genotyping of the control population of unaffected Doberman Pinschers. RESULTS: WGS and variant filtering identified an alteration in a gene associated with both deafness and vestibular disease in humans: protein tyrosine phosphatase, receptor type Q (PTPRQ). There was a homozygous A insertion at CFA15: 22 989 894, causing a frameshift mutation in exon 39 of the gene. This insertion is predicted to cause a protein truncation with a premature stop codon occurring after position 2054 of the protein sequence that causes 279 C-terminal amino acids to be eliminated. Prevalence of the variant was 1.5% in a cohort of 202 unaffected Doberman Pinschers; all unaffected Doberman Pinschers were heterozygous or heterozygous for the reference allele. CONCLUSION AND CLINICAL IMPORTANCE: We report the identification of a genetic alteration on the PTPRQ gene that is associated with congenital hearing and vestibular disorder in a young Doberman Pinscher dog.

Identification of Novel PTPRQ and MYO1A Mutations in An Iranian Pedigree with Autosomal Recessive Hearing Loss.

Autosomal recessive non-syndromic hearing loss (ARNSHL) is defined as a genetically heterogeneous disorder. The aim of the present study was to screen for pathogenic variants in an Iranian pedigree with ARNSHL. Next-generation targeted sequencing of 127 deafness genes in the proband detected two novel variants, a homozygous missense variant in PTPRQ (c.2599 T>C, p.Ser867Pro and a heterozygous missense variant in MYO1A (c.2804 T>C, p.Ile935Thr), both of which were absent in unaffected sibs and two hundred unaffected controls. Our results suggest that the homozygous PTPRQ variant maybe the pathogenic variant for ARNSHL due to the recessive nature of the disorder. Nevertheless, the heterozygous MYO1A may also be involved in this disorder due to the multigenic pattern of ARNSHL. Our data extend the mutation spectrum of PTPRQ and MYO1A, and have important implications for genetic counseling in unaffected sibs of this family. In addition, PTPRQ and MYO1A pathogenic variants have not to date been reported in the Iranian population.

High PTPRQ Expression and Its Relationship to Expression of PTPRZ1 and the Presence of KRAS Mutations in Colorectal Cancer Tissues.

BACKGROUND: The risk of sporadic colorectal cancer (CRC) is strongly influenced by Iifestyle, environmental and genetic factors. Protein tyrosine phosphatases belong to a group of enzymes whose role in CRC has not yet been intensively studied. They play an important role in activation/de-activation of many enzymes, influencing cell biology by catalyzing reactions opposing those catalyzed by kinases. Protein tyrosine phosphatase receptor-like type Q (PTPRQ) and protein tyrosine phosphatase receptor-like type Z polypeptide 1 (PTPRZ1) have both been shown to be important in development of many cancer types including CRC. MATERIALS AND METHODS: The expression level of PTPRQ and PTPRZ1 was determined by real-time polymerase chain reaction in 16 CRC tissues obtained from patients diagnosed with adenocarcinoma coli. RESULTS: We revealed a high level of PTPRQ expression (p=0.0080), as well as an association between expression levels of PTPRQ and PTPRZ1 (p<0.0001). Moreover PTPRQ expression was higher in tissues presenting with Kirsten rat sarcoma viral oncogene homolog (KRAS) mutation (p=0.0293). CONCLUSION: We confirmed the contribution of PTPRZ1 and especially PTPRQ in CRC development, supporting the hypothesis that PTPRQ is a candidate oncogene, playing a crucial role in phosphorylation/dephosphorylation signaling pathways.

CLIC5 stabilizes membrane-actin filament linkages at the base of hair cell stereocilia in a molecular complex with radixin, taperin, and myosin VI.

Chloride intracellular channel 5 protein (CLIC5) was originally isolated from microvilli in complex with actin binding proteins including ezrin, a member of the Ezrin-Radixin-Moesin (ERM) family of membrane-cytoskeletal linkers. CLIC5 concentrates at the base of hair cell stereocilia and is required for normal hearing and balance in mice, but its functional significance is poorly understood. This study investigated the role of CLIC5 in postnatal development and maintenance of hair bundles. Confocal and scanning electron microscopy of CLIC5-deficient jitterbug (jbg) mice revealed progressive fusion of stereocilia as early as postnatal day 10. Radixin (RDX), protein tyrosine phosphatase receptor Q (PTPRQ), and taperin (TPRN), deafness-associated proteins that also concentrate at the base of stereocilia, were mislocalized in fused stereocilia of jbg mice. TPRQ and RDX were dispersed even prior to stereocilia fusion. Biochemical assays showed interaction of CLIC5 with ERM proteins, TPRN, and possibly myosin VI (MYO6). In addition, CLIC5 and RDX failed to localize normally in fused stereocilia of MYO6 mutant mice. Based on these findings, we propose a model in which these proteins work together as a complex to stabilize linkages between the plasma membrane and subjacent actin cytoskeleton at the base of stereocilia.