Isolation of a Testis-Specific cDNA on Chromosome 17q from a Region Adjacent to the Breakpoint of t(12, 17) Observed in a Patient with Acampomelic Campomelic Dysplasia and Sex Reversal

Abstract

Campomelic dysplasia (CMPD), a rare congenital disorder, is characterized by a variety of skeletal anomalies, low-set ears and, in nearly half of genotypical-male patients, sex reversal. Observations of chromosomal translocations involving chromosome 17q24-q25 in several CMPD patients have implied that disruption of one or more genes in the breakpoint region is responsible for this disease. Using fluorescence in situ hybridization, we mapped the chromosome-17 breakpoint in a patient with acampomelic CMPD and sex reversal, who carries a de novo constitutional t(12;17) translocation, between two known cosmid markers in the 17q24-q25 region. Through positional cloning, we isolated a 3.5 kb cDNA that is located at a close but distinct position from the SOX9 gene, from the region surrounding this breakpoint. Its mRNA, approximately 3.7 kb long, was expressed specifically in testis among 16 adult tissues examined by Northern blot analysis. As we were unable to find any long open reading frame in the 3.5 kb cDNA sequence or to detect any peptide following an in vitro translation experiment using RNA transcribed from this cDNA, we speculate that this gene may play a critical role in differentiation or sex determination as a functional RNA.

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

“…While a clear genotypephenotype correlation could not be established to date, the acampomelic form appears to be mild by comparison. Of 11 ACD cases in the literature in whom SOX9 mutations were reported, five carry missense mutations (Friedrich, et al, 2000;Michel-Calemard, et al, 2004;Moog, et al, 2001;Sock, et al, 2003; while the other six carry deletions or rearrangements directly affecting a cis-acting element upstream of the SOX9 coding region but not the coding region itself (Hill-Harfe, et al, 2005;Lecointre, et al, 2009;Leipoldt, et al, 2007;Ninomiya, et al, 1996;Velagaleti, et al, 2005). Of 8 cases with ACD and a XY karyotype, 4 cases (1 balanced translocation with a breakpoint upstream from the coding region, 3 missense mutations) do not show sex reversal.…”

The Evf-2 noncoding RNA is transcribed from the Dlx-5/6 ultraconserved region and functions as a Dlx-2 transcriptional coactivator

“…However, recent discoveries have added several new types of RNAs to this list, including microRNA (miRNA, putative translational regulatory gene family), small interfering RNA (siRNA), and small nucleolar RNA (snoRNA, involved in rRNA modification). Among this growing list of ncRNAs is a group associated with human disease: DGCR5, breakpoint region in DiGeorge syndrome (Sutherland et al 1996); KkvLQTA-AS, implicated in Beckwith-Wiedeman syndrome (Lee et al 1999); SCA8, spinocerebellar ataxia type 8 (Nemes et al 2000); and CMPDassociated RNA, Campomelic dysplasia (Ninomiya et al 1996). As the number of non-mRNA functional RNAs increases, there is likely to be more acceptance that such RNAs may play important regulatory roles with their alterations resulting in human diseases.…”

Molecular cytogenetic detection of 9q34 breakpoints associated with nail patella syndrome

“…27 In campomelic dysplasia, all studied translocation breakpoints have so far been mapped at considerable distances (up to at least 300 kb) from the target gene SOX9. [23][24][25][26] An interesting point is that the clinical features of campomelic dysplasia in most of these translocation cases are less severe than observed for intragenic SOX9 mutations. With regard to the present study, this could have implications for the 1;9-translocation patient who only showed a few of the features of NPS1.…”

“…The tentative assumption is that one or At present, we can only speculate about the possible involvement of position effects in NPS1. The likely involvement of position effects has been shown to be associated with a growing number of balanced translocations associated with congenital disorders, including aniridia, 19,20 X-linked deafness, 21 holoprosencephaly 22 and campomelic dysplasia [23][24][25][26] with the common theme that dosage-sensitive transcription factors are involved. 27 In campomelic dysplasia, all studied translocation breakpoints have so far been mapped at considerable distances (up to at least 300 kb) from the target gene SOX9.…”