Two novel mutations of PAX3 and SOX10 were characterized as genetic causes of Waardenburg Syndrome

Abstract

BackgroundThe objective of this study was to investigate the genetic causes of two probands diagnosed as Waardenburg syndrome (WS type I and IV) from two unrelated Chinese families.MethodsPAX3 and SOX10 were the main pathogenic genes for WS type I (WS I) and IV (WS IV), respectively; all coding exons of these genes were sequenced on the two probands and their family members. Luciferase reporter assay and co‐immunoprecipitation (CO‐IP) were conducted to verify potential functional outcomes of the novel mutations.ResultsThe first proband is a 9 years old girl diagnosed with WS I. A novel PAX3 heterozygous mutation of c.372‐373delGA (p.N125fs) was identified, which results in a frameshift and truncation of PAX3 protein. In family II, a 2 years old girl was diagnosed with WS IV, and Sanger sequencing revealed a de novo SOX10 mutation of c.1114insTGGGGCCCCCACACTACACCGAC (p.Q372fs), a frameshift mutation that extends the amino acid chain of SOX10 protein. Functional studies indicated that the novel mutation of SOX10 had no effects on the interaction of SOX10 and PAX3, but reduced transactivate capacity of melanocyte inducing transcription factor (MITF) promoter. Both PAX3 and SOX10 mutation‐induced defects of MITF transcription might contribute to the WS pathogenesis.ConclusionWe revealed a novel mutation in PAX3 and a de novo mutation in SOX10, which might account for the underlying pathogenesis of WS. This study expands the database of both PAX10 and PAX3 mutations and improves our understanding of the causes of WS.

Identification of eight novel variants acrossPAX3, SOX10, EDNRBandMITFgenes in Waardenburg syndrome with next-generation sequencing

“…SOX10 encodes a TF critical to the early development of neural crest stem cells by promoting cell survival and maintaining multipotency [46, 47]. Moreover, SOX10 controls the development of melanocytes by regulating MITF expression in synergy with PAX3 [11]. Through modulation of RET expression, SOX10 determines the morphogenesis of the enteric nervous system (ENS) [48].…”

“…WS presents with a high degree of genetic heterogeneity. Six genes have been confirmed to cause WS: paired box 3 ( PAX3 ) [8], melanocyte inducing transcription factor ( MITF ) [9, 10], SRY-box transcription factor 10 ( SOX10 ) [5, 11], endothelin 3 ( EDN3 ) [12], endothelin receptor type B ( EDNRB ) [13], and snail family transcriptional repressor 2 ( SNAI2 ) [14]. Variants in PAX3 are primarily responsible for WS1 and WS3, while SOX10, EDN3 , and EDNRB variants are involved in WS4.…”

Four mutations in MITF, SOX10 and PAX3 genes were identified as genetic causes of waardenburg syndrome in four unrelated Iranian patients: case report

“…SOX10 possesses a dimerization domain (AA61-101), a DNA-binding high-mobility group (HMG) domain (101–180), a conserved domain in the center of the protein (233–306), and a transactivation domain (400–466) at the C-terminus. Mutations in SOX10 are associated with WS2E and WS4C (OMIM: 613,266), while mutations in SOX10 that are responsible for WS4 with neurological features referred to as PCWH (OMIM: 609,136) which patients may suffer from peripheral neuropathy, mental retardation, cerebellar ataxia, neonatal hypotonia and spasticity [ 5 , 14 , 46 – 48 ]. PCWH is mostly caused by truncating mutations in the last coding exon of SOX10 or less than 50–55 nucleotides upstream of the last coding exon, induce escaping the mutant mRNAs from the NMD pathway.…”

“…The PD and HD are DNA binding domains, while the TA domain mediates transcriptional regulation. The translated regions encode a 505-amino acid protein [ 5 , 19 , 48 , 50 , 51 ]. A previous functional study has demonstrated that the truncating mutation 1185 insTGA which removes a part of the transactivation domain of PAX3 reduced its effect on MITF promoter activation, and also its synergistic effect with SOX10 was completely lost.…”

Case Report: A Novel Gross Deletion in PAX3 (10.26 kb) Identified in a Chinese Family With Waardenburg Syndrome by Third-Generation Sequencing

“…WS is caused by the lack of melanophores in the eyes, skin, cochlea, and hair, which in itself originates from mutations in different genes affecting neural crest function (Alehabib et al, 2020 ). The known causative genes of WS include PAX3, MITF, WS2B, WS2C, SNAI2, EDNRB, EDN3, SOX10 , and TYR ; among them, PAX3 is the most classic, and its mutations or gross deletions produce WS1 or WS3 (Yu et al, 2020 ). To date, heterozygous mutations of PAX3 are commonly associated with WS1, whereas partial or total deletions of PAX3 are often observed in WS3 cases (Ahmed Jan et al, 2021 ).…”