Balkan Journal of Medical Genetics

DUPLICATION OF THE SOX3 GENE IN AN SRY-NEGATIVE 46,XX MALE WITH ASSOCIATED CONGENITAL ANOMALIES OF KIDNEYS AND THE URINARY TRACT: CASE REPORT AND REVIEW OF THE LITERATURE
Tasic V1, Mitrotti A2, Riepe FG3, Kulle AE3, Laban N1, Polenakovic M4, Plaseska-Karanfilska D4, Sanna-Cherchi S2, Kostovski M1, Gucev Z1,*
*Corresponding Author: Professor Dr. Zoran Gucev, University Children’s Hospital, Medical Faculty Skopje, ul. Majka Tereza 17, 1000 Skopje, Republic of Macedonia. Mobile: +389-70-279-742. E-mail: gucevz@ gmail.com
page: 81

DISCUSSION

There are four cases reported with SOX3 duplications in 46,XX SRY-negative males in the literature [26,27,41] (Table 1). Two of the 46,XX male patients, 30 and 26 years old, respectively, reported by Sutton et al. [26], had normal intelligence and growth; the third one had developmental delay, growth retardation and microcephaly. The patient described by Grinspon et al. [27] had normal growth and intelligence, but was affected by hypospadias and cryptorchidism, with ovotestis and hypoplastic testis. Histology analysis showed atrophic changes and loss of normal spermatogenesis. Our patient’s clinical phenotype was characterized by normal development and intelligence, DSD characterized by hypospadias and males genitalia with 46,XX karyotype, and, unique compared to all other reported patients in the literature, hypoplasia of the left kidney. Interestingly, our patient, as well as the patient described by by Grinspon et al. [27], both with karyotype 46,XX SRY-negative, were characterized by duplications involving the Xq27, encompassing the same genes: SOX3, the non coding RNA LINC00632, AK054921, CDR1 and the miRNA MIR320D2. The question is whether the kidney defect observed in our patient is biologically related to the duplication of SOX3 or the other genes in the CNV, or if it represents a coincidental finding. Analysis of publicly available expression data (www.gudmap.org) indicates high expression of Sox3 in the mouse developing bladder neck at embryonic day E13.5, thus suggesting a possible link to lower urinary tract malformations. The SOX3 gene is known to be regulated by PBX1 through direct interaction with its transcription binding site [42]. Interestingly, another patient with renal hypodysplasia from our cohort, was found to carry a de novo 0.51 kb deletion affecting PBX1 [28]. Inactivation of Pbx1 in the mouse results in urinary malformations including renal agenesis and hypodysplasia [43]. Finally, a recent report implicates haploinsufficiency of PBX1 in the pathogenesis of syndromic forms of congenital anomalies of the kidney and urinary tract [44]. These data provide plausible links between SOX3 gene dosage and kidney malformations. Formal proof of a causal link will require additional genetic and functional data. It is noteworthy that the current and reported SOX3 duplications are below the detection threshold of standard karyotype and were found only by analyzing CNVs using DNA microarrays. Therefore, it is important to convey that all 46,XX SRY-negative males should be screened for SOX3 duplications with DNA microarrays. We report a case of an 11-year-old male with a duplication of chromosome Xq27, involving SOX3, and leading to a male sex reversal and, possibly, kidney hypoplasia. This is the second case of 46,XX SRY-negative affected by DSD and characterized by CNV involving the SOX3 locus, described so far. We speculate that the genomic duplication involving SOX3 could be responsible not only for pituitary hormone deficiencies in humans and male sex reversal, but also for CAKUT. All 46,XX SRY-negative patients, should be screened for duplications affecting SOX3. Declaration of Interest. The authors report no conflicts of interest. The authors alone are responsible for the content and writing of this article. Funding. This study was supported by a grant from the International Centre for Genetic Engineering and Biotechnology, ICGEB Ref. No. CRP/MAC13-01.

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