SOX10 Mutations Research Articles

Heterozygous SOX9 Mutations Allowing for Residual DNA-binding and Transcriptional Activation Lead to the Acampomelic Variant of Campomelic Dysplasia

Campomelic dysplasia is a malformation syndrome with multiple symptoms including characteristic shortness and bowing of the long bones (campomelia). CD, often lethal due to airway malformations, is caused by heterozygous mutations in SOX9, an SRY-related gene regulating testis and chondrocyte development including expression of many cartilage genes such as type II collagen. Male to female sex reversal occurs in the majority of affected individuals with an XY karyotype. A mild form without campomelia exists, in which sex-reversal may be also absent. We report here two novel SOX9 missense mutations in a male (c.495C>G; p.His165Gln) and a female (c.337A>G; p.Met113Val) within the DNA-binding domain leading to non-lethal acampomelic CD. Functional analyses of mutant proteins demonstrate residual DNA-binding and transactivation of SOX9-regulated genes. Combining our data and reports from the literature we postulate a genotype-phenotype correlation: SOX9 mutations allowing for residual function lead to a mild form of CD in which campomelia and sex reversal may be absent.

Identification of SOX9 Interaction Sites in the Genome of Chondrocytes

BackgroundOur previous work has provided strong evidence that the transcription factor SOX9 is completely needed for chondrogenic differentiation and cartilage formation acting as a “master switch” in this differentiation. Heterozygous mutations in SOX9 cause campomelic dysplasia, a severe skeletal dysmorphology syndrome in humans characterized by a generalized hypoplasia of endochondral bones. To obtain insights into the logic used by SOX9 to control a network of target genes in chondrocytes, we performed a ChIP-on-chip experiment using SOX9 antibodies.Methodology/Principal FindingsThe ChIP DNA was hybridized to a microarray, which covered 80 genes, many of which are involved in chondrocyte differentiation. Hybridization peaks were detected in a series of cartilage extracellular matrix (ECM) genes including Col2a1, Col11a2, Aggrecan and Cdrap as well as in genes for specific transcription factors and signaling molecules. Our results also showed SOX9 interaction sites in genes that code for proteins that enhance the transcriptional activity of SOX9. Interestingly, a strong SOX9 signal was also observed in genes such as Col1a1 and Osx, whose expression is strongly down regulated in chondrocytes but is high in osteoblasts. In the Col2a1 gene, in addition to an interaction site on a previously identified enhancer in intron 1, another strong interaction site was seen in intron 6. This site is free of nucleosomes specifically in chondrocytes suggesting an important role of this site on Col2a1 transcription regulation by SOX9.Conclusions/SignificanceOur results provide a broad understanding of the strategies used by a “master” transcription factor of differentiation in control of the genetic program of chondrocytes.

Loss of Sox9 in the periotic mesenchyme affects mesenchymal expansion and differentiation, and epithelial morphogenesis during cochlea development in the mouse

Sox9 encodes an HMG-domain transcription factor that is critically required in numerous developmental processes such as chondrogenesis and otic placode formation. Here, we show that Sox9 is expressed in the mesenchyme surrounding the developing cochlea in the mouse suggesting that Sox9 may also control development of the otic fibrocyte compartment and the surrounding otic capsule. Tissue-specific inactivation of Sox9 in the periotic mesenchyme using a Tbx18 Cre mouse line results in arrest of early chondrogenesis and consequently, in a lack of cochlear otic capsule formation. Furthermore, loss of Sox9 severely compromises expansion, differentiation and remodeling of the otic fibrocyte compartment. Early cell proliferation defects in the entire periotic mesenchyme of Sox9-deficient inner ears suggest a cell-autonomous function of Sox9 for the development of the inner mesenchymal compartment. Abnormal cochlear duct morphogenesis in Sox9 mutants including disruption of the coiling process is tightly associated with the onset of mesenchymal defects whereas the absence of major differentiation defects in the otic epithelium suggests that Sox9-dependent mesenchymal signals primarily control epithelial morphogenesis.

SOX10 structure-function analysis in the chicken neural tube reveals important insights into its role in human neurocristopathies

The HMG-domain containing transcription factor Sox10 is essential for neural crest (NC) development and for oligodendrocyte differentiation. Heterozygous SOX10 mutations in humans lead to corresponding defects in several NC-derived lineages and to leukodystrophies. Disease phenotypes range from Waardenburg syndrome and Waardenburg-Hirschsprung disease to Peripheral demyelinating neuropathy, Central dysmyelination, Waardenburg syndrome and Hirschsprung disease (PCWH). The phenotypic variability can partly be explained by the action of modifier genes, but is also influenced by the mutation that leads to haploinsufficiency in some and to mutant SOX10 proteins with altered properties in other cases. Here, we used in ovo electroporation in the developing neural tube of chicken to determine which regions and properties of SOX10 are required for early NC development. We found a strict reliance on the DNA-binding activity and the presence of the C-terminal transactivation domain and a lesser influence of the dimerization function and a conserved domain in the center of the protein. Intriguingly, dominant-negative effects on early NC development were mostly observed for truncated SOX10 proteins whose production in patients is probably prevented by nonsense-mediated decay. In contrast, mutant SOX10 proteins that occur in patients were usually inactive. Any dominant negative activity which some of these mutants undoubtedly possess must, therefore, be restricted to single NC-derived cell lineages or oligodendrocytes at later times. This contributes to the phenotypic variability of human SOX10 mutations.

Genetic interaction between Sox10 and Zfhx1b during enteric nervous system development

The involvement of SOX10 and ZFHX1B in Waardenburg–Hirschsprung disease (hypopigmentation, deafness, and absence of enteric ganglia) and Mowat–Wilson syndrome (mental retardation, facial dysmorphy and variable congenital malformations including Hirschsprung disease) respectively, highlighted the importance of both transcription factors during enteric nervous system (ENS) development. The expression and function of SOX10 are now well established, but those of ZFHX1B remain elusive. Here we describe the expression profile of Zfhx1b and its genetic interactions with Sox10 during mouse ENS development. Through phenotype analysis of Sox10;Zfhx1b double mutants, we show that a coordinated and balanced interaction between these two genes is required for normal ENS development. Double mutants present with more severe ENS defects due to decreased proliferation of enteric progenitors and increased neuronal differentiation from E11.5 onwards. Thus, joint activity between these two transcription factors is crucial for proper ENS development and our results contribute to the understanding of the molecular basis of ENS defects observed both in mutant mouse models and in patients carrying SOX10 and ZFHX1B mutations.

Involvement of SOX10 in the pathogenesis of Hirschsprung disease: report of a truncating mutation in an isolated patient

SOX10 protein is a key transcription factor during neural crest development. Mutations in SOX10 are associated with several neurocristopathies such as Waardenburg syndrome type IV (WS4), a congenital disorder characterized by the association of hearing loss, pigmentary abnormalities, and absence of ganglion cells in the myenteric and submucosal plexus of the gastrointestinal tract, also known as aganglionic megacolon or Hirschsprung disease (HSCR). Several mutations at this locus are known to cause a high percentage of WS4 cases, but no SOX10 mutations had been ever reported associated to isolated HSCR patient. Therefore, nonsyndromic HSCR was initially thought not to be associated to mutations at this particular locus. In the present study, we describe the evaluation of the SOX10 gene in a series of 196 isolated HSCR cases, the largest patient series evaluated so far, and report a truncating c.153-155del mutation. This is the first time that a SOX10 mutation is detected in an isolated HSCR patient, which completely changes the scenario for the implications of SOX10 mutations in human disease, giving us a new tool for genetic counseling.

Patient Reports: Two Novel Frameshift Mutations in the SOX9 Gene in Two Patients with Campomelic Dysplasia who showed Long-Term Survival

Campomelic dysplasia (CD) is a rare and usually fatal congenital skeletal disorder with respiratory failure. The SOX9 gene has been cloned as a candidate gene for CD. Here, we report the cases of 2 Japanese patients with CD who have survived for over 5 years. Molecular investigations revealed novel frameshift mutations in SOX9 in these patients; a single G insertion in 1 allele at nucleotide 261 (261-262insG) and a single C insertion in 1 allele at nucleotide 888 (888-889insC). The predicted protein of 261-262insG may lack more than 80% composition of the normal SOX9 protein, including the SRY high mobility group (HMG) domain and the transactivation (TA) domain; the predicted protein of 888-889insC may not contain the normal TA domain. Although it has been reported that most patients with CD die during the neonatal period, our patients have survived for a long time, despite putative severely impaired SOX9 proteins.

Novel SOX2 mutations and genotype–phenotype correlation in anophthalmia and microphthalmia

SOX2 represents a High Mobility Group domain containing transcription factor that is essential for normal development in vertebrates. Mutations in SOX2 are known to result in a spectrum of severe ocular phenotypes in humans, also typically associated with other systemic defects. Ocular phenotypes include anophthalmia/microphthalmia (A/M), optic nerve hypoplasia, ocular coloboma and other eye anomalies. We screened 51 unrelated individuals with A/M and identified SOX2 mutations in the coding region of the gene in 10 individuals. Seven of the identified mutations are novel alterations, while the remaining three individuals carry the previously reported recurrent 20-nucleotide deletion in SOX2, c.70del20. Among the SOX2-positive cases, seven patients had bilateral A/M and mutations resulting in premature termination of the normal protein sequence (7/38; 18% of all bilateral cases), one patient had bilateral A/M associated with a single amino acid insertion (1/38; 3% of bilateral cases), and the final two patients demonstrated unilateral A/M associated with missense mutations (2/13; 15% of all unilateral cases). These findings and review of previously reported cases suggest a potential genotype/phenotype correlation for SOX2 mutations with missense changes generally leading to less severe ocular defects. In addition, we report a new familial case of affected siblings with maternal mosaicism for the identified SOX2 mutation, which further underscores the importance of parental testing to provide accurate genetic counseling to families.

Sox10 promotes the survival of cochlear progenitors during the establishment of the organ of Corti

Transcription factors of the SoxE family are critical players that underlie various embryological processes. However, little is known about their function during inner ear development. Here, we show that Sox10 is initially expressed throughout the otic vesicle epithelium and becomes later restricted to supporting cells as cell differentiation proceeds in the organ of Corti. Morphological analyses of Sox10 mutant mice reveal a significant shortening of the cochlear duct likely resulting from the progressive depletion of cochlear progenitors. While Sox10 appears dispensable for the differentiation and patterning of the inner ear prosensory progenitors, our data support a critical role for this transcription factor in the promotion of their survival. We provide genetic evidences that Sox10, in a concentration-dependant manner, could play a role in the regulation of Jagged1, a gene known to be important for inner ear prosensory development. Together, our results demonstrate that Sox10 regulates the biology of early cochlear progenitors during inner ear development, but, in contrast to neural crest-derived cells, this transcription factor is dispensable for their differentiation. Evidence also suggests that this effect occurs via the activation of the Jagged1 gene.

Hippocampal development and neural stem cell maintenance require Sox2-dependent regulation of Shh

Neural stem cells (NSCs) are controlled by diffusible factors. The transcription factor Sox2 is expressed by NSCs and Sox2 mutations in humans cause defects in the brain and, in particular, in the hippocampus. We deleted Sox2 in the mouse embryonic brain. At birth, the mice showed minor brain defects; shortly afterwards, however, NSCs and neurogenesis were completely lost in the hippocampus, leading to dentate gyrus hypoplasia. Deletion of Sox2 in adult mice also caused hippocampal neurogenesis loss. The hippocampal developmental defect resembles that caused by late sonic hedgehog (Shh) loss. In mutant mice, Shh and Wnt3a were absent from the hippocampal primordium. A SHH pharmacological agonist partially rescued the hippocampal defect. Chromatin immunoprecipitation identified Shh as a Sox2 target. Sox2-deleted NSCs did not express Shh in vitro and were rapidly lost. Their replication was partially rescued by the addition of SHH and was almost fully rescued by conditioned medium from normal cells. Thus, NSCs control their status, at least partly, through Sox2-dependent autocrine mechanisms.

20-P002 Pre-enteric migration of sacral neural crest cells is affected in Dominant megacolon embryos

Our previous study showed that mouse neural crest cells (NCCs) from the sacral level were able to migrate from the dorsal neural tube over long distances to enter the hindgut. In the present study, we sought to determine whether Sox10 mutation affected the migration of sacral NCCs prior to their entry to the hindgut. Dominant megacolon (Dom) mice with a spontaneous mutation of Sox10, and experimental techniques including cell labelling, whole embryo culture and multiple immunohistochemical staining were used. We found that in wild type embryos, sacral NCCs caudal to somite 24 began their migration from the neural tube at E9.5, started to aggregate on two sides of the hindgut to form pelvic ganglia at E11.5 and by around E14.0 entered the hindgut at S2 and S3 vertebral levels. In Sox10Dom heterozygous mutants, sacral NCCs migrated along the same spatio-temporal pathway, although the number of migrating sacral NCCs was significantly reduced. In Sox10Dom homozygotes, the number of migrating sacral NCCs was further reduced and no NCCs reached the pelvic ganglia region. TUNEL assay did not reveal any significant increase in sacral NCC death in either Sox10Dom/+ or Sox10Dom/Dom mutants. Our observations indicate that the Sox10 mutation in Dom embryos affects the migration of sacral NCC before they enter the hindgut by reducing the number of migrating sacral NCCs.

Frequent mutations in the MITF pathway in melanoma

Microphthalmia-associated transcription factor (MITF) is involved in melanocyte cell development, pigmentation and neoplasia. To determine whether MITF is somatically mutated in melanoma, we compared the sequence of MITF from primary and metastatic lesions to patient-matched normal DNA. In the 50 metastatic melanoma tumor lines analysed, we discovered four samples that had genomic amplifications of MITF and four that had MITF mutations in the regions encoding the transactivation, DNA binding or basic, helix-loop-helix domains. Sequence analysis for SOX10, a transcription factor, which both acts upstream of MITF and synergizes with MITF, identified an additional three samples with frameshift or nonsense mutations. Microphthalmia-associated transcription factor and SOX10 were found to be mutated in a mutually exclusive fashion, possibly suggesting disruption in a common genetic pathway. Taken together we found that over 20% of the metastatic melanoma cases had alterations in the MITF pathway. We show that the MITF pathway is also altered in primary melanomas: 2/26 demonstrated mutations in MITF and 6/55 demonstrated mutations in SOX10. Our findings suggest that altered MITF function during melanomagenesis can be achieved by MITF amplification, MITF single base substitutions or by mutation of its regulator SOX10.

Upwards and onwards

The success of a journal is ultimately tied to its appeal to its readership and potential authors. Over the past few years, by publishing News and Views on high profile papers in the field, inserting ‘Melanoma’ into the title and being adopted as the official journal of the Society for Melanoma Research, and generally acting as a focus and forum for debate on key issues, Pigment Cell & Melanoma Research has increased its readership and is now attracting papers from groups that until recently would have submitted elsewhere. The increased awareness of the journal means that papers published in pcr are more widely read and research into pigment cell biology is gaining a higher profile. The most visible manifestation of a journal’s success is the impact factor, used by publishers to trumpet the success of a journal, and by authors as a key determinant of where to submit. With that in mind, it is again satisfying that the impact factor of this journal has risen yet again, to 4.634. The strong upward trend in impact factor reflects increased citation of papers published in pcr and suggests that the journal is achieving its ambition of serving the research community by publishing papers and reviews of increasing significance to the field. The fact that many of the most cited papers and reviews are in the melanoma field also suggests that the decision to court a melanoma audience has benefited the journal as a whole and is making a substantial contribution to its success. One of the most obvious manifestations of genetic diversity is the range of human pigmentation phenotypes as illustrated by this month’s striking cover. It is widely believed that early hominids originated as a hair covered species in Africa, lacking epidermal pigmentation except in exposed sites and that pigmentation evolved to protect skin against photodamage as hair cover diminished. The migration of humans out of Africa subsequently led to a gradual decrease in levels of constitutive pigmentation as a result of the evolutionary pressures arising from the need to synthesise vitamin D. However, the fact that pigmented melanocytes are present in a wide range of sites that are not sun exposed suggests that melanin-loaded pigment cells may have a range of functions not directly related to UV-irradiation. The hypothesis from Elias et al. explores the possibility that stress to the epidermis also contributed substantially to the origins of human pigmentation. Since its isolation in 1994, the gene encoding the microphthalmia-associated transcription factor Mitf has assumed centre stage as a key factor controlling melanocyte development and differentiation. Over recent years, it has also been implicated as a major regulator of cell cycle progression and metastatic potential. Given its importance and its regulation by the MAPkinase and Wnt/β-catenin signaling pathways implicated in both developmental control of the melanocyte lineage and melanoma progression, it seemed inevitable that genetic lesions affecting the MITF gene would be found in melanoma. That prophecy was fulfilled with the observation that amplification of the MITF gene occurs in many melanoma patients, though interestingly even a 100-fold amplification only led to around 1.5-fold increase in MITF protein levels. Nevertheless, the amplification of the MITF gene spurred the quest to find more subtle genetic alterations that would affect MITF activity and consequently melanoma behavior. Now, in this issue, Cronin et al. report that MITF is mutated at several residues in melanoma that lead to altered MITF function. The paper, featured in a News and Views by David Fisher, also highlights mutations in Sox10, a key regulator of MITF expression. Together, the evidence suggests that de-regulation of MITF function or expression is a major determinant of melanoma progression and lends support to the idea that understanding more of the controls operating on MITF may open novel therapeutic avenues.

Sox7 and Sox17 are strain-specific modifiers of the lymphangiogenic defects caused by Sox18 dysfunction in mice

Developmental defects caused by targeted gene inactivation in mice are commonly subject to strain-specific modifiers that modulate the severity of the phenotype. Although several genetic modifier loci have been mapped in mice, the gene(s) residing at these loci are mostly unidentified, and the molecular mechanisms of modifier action remain poorly understood. Mutations in Sox18 cause a variable phenotype in the human congenital syndrome hypotrichosis-lymphedema-telangiectasia, and the phenotype of Sox18-null mice varies from essentially normal to completely devoid of lymphatic vasculature and lethal, depending on the strain of the mice, suggesting a crucial role for strain-specific modifiers in this system. Here we show that two closely related Group F Sox factors, SOX7 and SOX17, are able to functionally substitute for SOX18 in vitro and in vivo. SOX7 and SOX17 are not normally expressed during lymphatic development, excluding a conventional redundancy mechanism. Instead, these genes are activated specifically in the absence of SOX18 function, and only in certain strains. Our studies identify Sox7 and Sox17 as modifiers of the Sox18 mutant phenotype, and reveal their mechanism of action as a novel mode of strain-specific compensatory upregulation.

Mutations in the Newly Identified RAX Regulatory Sequence Are Not a Frequent Cause of Micro/Anophthalmia

Microphthalmia and anophthalmia are at the severe end of the spectrum of abnormalities in ocular development. A few genes (SOX2, OTX2, RAX, and CHX10) have been implicated in isolated micro/anophthalmia, but causative mutations of these genes explain less than a quarter of these developmental defects. A specifically conserved SOX2/OTX2-mediated RAX expression regulatory sequence has recently been identified. We postulated that mutations in this sequence could lead to micro/anophthalmia, and thus we performed molecular screening of this regulatory element in patients suffering from micro/anophthalmia. Fifty-one patients suffering from nonsyndromic microphthalmia (n = 40) or anophthalmia (n = 11) were included in this study after negative molecular screening for SOX2, OTX2, RAX, and CHX10 mutations. Mutation screening of the RAX regulatory sequence was performed by direct sequencing for these patients. No mutations were identified in the highly conserved RAX regulatory sequence in any of the 51 patients. Mutations in the newly identified RAX regulatory sequence do not represent a frequent cause of nonsyndromic micro/anophthalmia.

Novel SOX2 partner-factor domain mutation in a four-generation family

Anophthalmia (no eye), microphthalmia (small eye) and associated ocular developmental anomalies cause significant visual handicap. In most cases the underlying genetic cause is unknown, but mutations in some genes, such as SOX2, cause ocular developmental defects, particularly anophthalmia, in a subset of patients. Here, we describe a four-generation family with a p.Asp123Gly mutation in the highly conserved partner-factor interaction region of the SOX2 protein, which is important for cell-specific actions of SOX2. The proband in this family has bilateral anophthalmia and several other family members have milder ocular phenotypes, including typical optic fissure coloboma. Expression studies indicate that Sox2 is expressed in the eye at the site of closure of the optic fissure during development. The SOX2 mutation in this family implicates the partner-factor interaction region of SOX2 in contributing to the specificity of SOX2 action in optic fissure closure. Our findings indicate that investigation of SOX2 in a broad range of eye anomaly patients aids in the determination of particular functions of SOX2 in development.

Aplasia of cochlear nerves and olfactory bulbs in association with SOX10 mutation

A 17-month-old boy was referred with profound sensorineural hearing loss (SNHL), severe visual impairment and developmental delay. Neuroimaging identified hypomyelination and cochlear nerve aplasia. He was noted to have fair skin and hair and multiple areas of cutaneous hyperpigmentation. Previous investigations including karyotype, array comparative genomic hybridization (aCGH) and a full metabolic screen were normal. A novel missense mutation of the highly conserved high mobility group (HMG) domain of SOX10 was identified (Q174P:c.521A>C). This case represents the first description of aplasia of the cochlear nerve due to a SOX10 mutation.

A novel SOX9 mutation, 972delC, causes 46,XY sex-reversed campomelic dysplasia with nephrocalcinosis, urolithiasis, and dysgerminoma

An 8-year-old phenotypic female with campomelic dysplasia (CD) and 46,XY sex-reversal presented with renal colic. Medullary nephrocalcinosis, urolithiasis, and renal malrotation were diagnosed by computed tomographic scanning. Pelvic sonogram identified an enlarged left gonad. Genetic testing revealed a novel SOX9 heterozygous deletion of a cytosine at nucleotide 972 (972delC), causing a frameshift at codon 200, introducing a stop codon 18 codons further downstream (P200fsX218). At laparoscopic gonadectomy, a left dysgerminoma was removed. This first reported case of dysgerminoma in a sex-reversed patient with CD who also had urolithiasis stresses the importance of prophylactic gonadectomy and urologic evaluations in this susceptible population.

Expression profiling of zebrafish sox9 mutants reveals that Sox9 is required for retinal differentiation

The transcription factor gene Sox9 plays various roles in development, including differentiation of the skeleton, gonads, glia, and heart. Other functions of Sox9 remain enigmatic. Because Sox9 protein regulates expression of target genes, the identification of Sox9 targets should facilitate an understanding of the mechanisms of Sox9 action. To help identify Sox9 targets, we used microarray expression profiling to compare wild-type embryos to mutant embryos lacking activity for both sox9a and sox9b, the zebrafish co-orthologs of Sox9. Candidate genes were further evaluated by whole-mount in situ hybridization in wild-type and sox9 single and double mutant embryos. Results identified genes expressed in cartilage ( col2a1a and col11a2), retina ( calb2a, calb2b, crx, neurod, rs1, sox4a and vsx1) and pectoral fin bud ( klf2b and EST AI722369) as candidate targets for Sox9. Cartilage is a well-characterized Sox9 target, which validates this strategy, whereas retina represents a novel Sox9 function. Analysis of mutant phenotypes confirmed that Sox9 helps regulate the number of Müller glia and photoreceptor cells and helps organize the neural retina. These roles in eye development were previously unrecognized and reinforce the multiple functions that Sox9 plays in vertebrate development.

A zebrafish model for Waardenburg syndrome type IV reveals diverse roles for Sox10 in the otic vesicle.

In humans, mutations in the SOX10 gene are a cause of the auditory-pigmentary disorder Waardenburg syndrome type IV (WS4) and related variants. SOX10 encodes an Sry-related HMG box protein essential for the development of the neural crest; deafness in WS4 and other Waardenburg syndromes is usually attributed to loss of neural-crest-derived melanocytes in the stria vascularis of the cochlea. However, SOX10 is strongly expressed in the developing otic vesicle and so direct roles for SOX10 in the otic epithelium might also be important. Here, we examine the otic phenotype of zebrafish sox10 mutants, a model for WS4. As a cochlea is not present in the fish ear, the severe otic phenotype in these mutants cannot be attributed to effects on this tissue. In zebrafish sox10 mutants, we see abnormalities in all otic placodal derivatives. Gene expression studies indicate deregulated expression of several otic genes, including fgf8, in sox10 mutants. Using a combination of mutant and morphant data, we show that the three sox genes belonging to group E (sox9a, sox9b and sox10) provide a link between otic induction pathways and subsequent otic patterning: they act redundantly to maintain sox10 expression throughout otic tissue and to restrict fgf8 expression to anterior macula regions. Single-cell labelling experiments indicate a small and transient neural crest contribution to the zebrafish ear during normal development, but this is unlikely to account for the strong defects seen in the sox10 mutant. We discuss the implication that the deafness in WS4 patients with SOX10 mutations might reflect a haploinsufficiency for SOX10 in the otic epithelium, resulting in patterning and functional abnormalities in the inner ear.