Variable Expression of Campomelic Dysplasia in a Father and his 46, XY Daughter

Savarirayan, Ravi; Robertson, Stephen; Bankier, Agnes; Rogers, John G.

doi:10.1080/15227950307695

Cited by 19 publications

(11 citation statements)

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“…Sensorineural hearing loss has been reported in the surviving CD patients, suggesting a role of SOX9 in inner ear development (Savarirayan et al, 2003). Various studies in Xenopus (Saint-Germain et al, 2004; Taylor and LaBonne, 2005), zebrafish (Yan et al, 2005) and mouse (Barrionuevo et al, 2008) have described the expression of SOX9 at the otic placode and/or vesicle stage and they have focused on uncovering the early role of SOX9 in inner ear development.…”

Section: Resultsmentioning

confidence: 99%

Differential and overlapping expression pattern of SOX2 and SOX9 in inner ear development

Mak

Szeto

Fritzsch

et al. 2009

Gene Expression Patterns

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The development of the inner ear involves complex processes of morphological changes, patterning and cell fate specification that are under strict molecular control. SOX2 and SOX9 are SOX family transcription factors that are involved in the regulation of one or more of these processes. Previous findings have shown early expression of SOX9 in the otic placode and vesicle at E8.5-E9.5. Here we describe in detail, the expression pattern of SOX9 in the developing mouse inner ear beyond the otocyst stage and compare it with that of SOX2 from E9.5 to E18.5 using double fluorescence immunohistochemistry. We found that SOX9 was widely expressed in the otic epithelium, periotic mesenchyme and cartilaginous otic capsule. SOX2 persistently marked the prosensory and sensory epithelia. During the development of the sensory epithelia, SOX2 was initially expressed in all prosensory regions and later in both the supporting and hair cells up to E15.5, when its expression in hair cells gradually diminished. SOX9 expression overlapped with that of SOX2 in the prosensory and sensory region until E14.5 when its expression was restricted to supporting cells. This initial overlap but subsequent differential expression of SOX2 and SOX9 in the sensory epithelia, suggest that SOX2 and SOX9 may have distinct roles in molecular pathways that direct cells towards different cell fates. KeywordsSOX2; SOX9; Inner ear; Otocyst; Hair cells; Sensory epithelia; Spiral ganglion Results and discussionThe mammalian inner ear is an intricate organ responsible for the perception of sound and balance. The mouse inner ear arises from a thickening of the surface ectoderm called otic placode located adjacent to rhombomeres 5 and 6 of the hindbrain (reviewed in Barald and Kelley, 2004). At E9.0, the otic placode invaginates to form the otic vesicle. Neuroblasts delaminate from the ventral thickening of the otic vesicle and form the otic ganglion which will become the sensory innervation of the inner ear (Rubel and Fritzsch, 2002 vesicle also undergoes a series of morphological changes until it reaches its mature shape by E17 (Morsli et al., 1998).The inner ear consists of six sensory organs: the three cristae in the semi-circular canals and the maculae in the utricle and saccule are responsible for vestibular function; the organ of Corti is responsible for auditory function. The sensory patches in these organs consist of hair and supporting cells. The development of sensory patches in the inner ear requires complex processes of prosensory cell specification and cell fate determination (reviewed in Fritzsch et al., 2006;Kelley, 2007), in which SOX2 and SOX9 are likely to be involved (see below).SOX2 and SOX9 are SOX family transcription factors characterized by a high mobility group (HMG) DNA-binding domain. Mutations in human SOX2 results in anophthalmia, a severe eye malformation, and some patients showed sensorineural hearing loss (Fantes et al., 2003;Hagstrom et al., 2005). SOX2 interacts with EYA1 for prosensory specification (Zou et al., 2008...

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Section: Resultsmentioning

confidence: 99%

Differential and overlapping expression pattern of SOX2 and SOX9 in inner ear development

Mak

Szeto

Fritzsch

et al. 2009

Gene Expression Patterns

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“…Germline mosaicism in one of the parents was also proposed as a cause of recurrent CD in a family described by Meyer et al [1997]. Savarirayan et al [2003] postulated that parents of individuals with CD should be examined for minimal manifestations of the disorder, which may represent phenotypic variability of the syndrome or somatic mosaicism.…”

Section: Discussionmentioning

confidence: 98%

Recurrent SOX9 deletion campomelic dysplasia due to somatic mosaicism in the father

Smyk¹,

Obersztyn²,

Nowakowska

et al. 2007

American J of Med Genetics Pt A

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Haploinsufficiency of SOX9, a master gene in chondrogenesis and testis development, leads to the semi-lethal skeletal malformation syndrome campomelic dysplasia (CD), with or without XY sex reversal. We report on two children with CD and a phenotypically normal father, a carrier of a somatic mosaic SOX9 deletion. This is the first report of a mosaic deletion of SOX9; few familial CD cases with germline and somatic mutation mosaicism have been described. Our findings confirm the utility of aCGH and indicate that for a more accurate estimate of the recurrence risk for a completely penetrant autosomal dominant disorder, parental somatic mosaicism should be considered in healthy parents.

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“…Individuals affected by this condition usually die shortly after birth because of respiratory distress; therefore, it has been difficult to evaluate the auditory capability of these individuals. However, reports of rare individuals that survived through adolescence (Houston et al, 1983) and adulthood (Savarirayan et al, 2003) indicate that they are affected with sensorineural deafness. Our results in Xenopus predict that hearing loss associated with campomelic dysplasia is likely to be the result of an early defect in the specification of the otic placode.…”

Section: Discussionmentioning

confidence: 99%

“…These symptoms have also been associated with deafness (Houston et al, 1983;Savarirayan et al, 2003), consistent with Sox9 expression in the otic epithelium of several species (Zhao et al, 1997;Ng et al, 1997;Spokony et al, 2002;Li et al, 2002;Liu et al, 2003). However, very little is known about the function of Sox9 during development of the auditory system.…”

Section: Introductionmentioning

confidence: 93%

Specification of the otic placode depends on Sox9 function inXenopus

et al. 2004

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The vertebrate inner ear develops from a thickening of the embryonic ectoderm, adjacent to the hindbrain, known as the otic placode. All components of the inner ear derive from the embryonic otic placode. Sox proteins form a large class of transcriptional regulators implicated in the control of a variety of developmental processes. One member of this family, Sox9, is expressed in the developing inner ear, but little is known about the early function of Sox9 in this tissue. We report the functional analysis of Sox9 during development of Xenopus inner ear. Sox9 otic expression is initiated shortly after gastrulation in the sensory layer of the ectoderm, in a bilateral patch of cells immediately adjacent to the cranial neural crest. In the otic placode, Sox9 colocalizes with Pax8 one of the earliest gene expressed in response to otic placode inducing signals. Depletion of Sox9 protein in whole embryos using morpholino antisense oligonucleotides causes a dramatic loss of the early otic placode markers Pax8 and Tbx2. Later in embryogenesis, Sox9 morpholino-injected embryos lack a morphologically recognizable otic vesicle and fail to express late otic markers (Tbx2, Bmp4,Otx2 and Wnt3a) that normally exhibit regionalized expression pattern throughout the otocyst. Using a hormone inducible inhibitory mutant of Sox9,we demonstrate that Sox9 function is required for otic placode specification but not for its subsequent patterning. We propose that Sox9 is one of the key regulators of inner ear specification in Xenopus.

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Variable Expression of Campomelic Dysplasia in a Father and his 46, XY Daughter

Cited by 19 publications

References 0 publications

Differential and overlapping expression pattern of SOX2 and SOX9 in inner ear development

Differential and overlapping expression pattern of SOX2 and SOX9 in inner ear development

Recurrent SOX9 deletion campomelic dysplasia due to somatic mosaicism in the father

Specification of the otic placode depends on Sox9 function inXenopus

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