A point mutation, R59G, within the HMG-SRY box in a female 45,X/46,X, psu dic(Y)(pter→q11::q11→pter)

Abstract

We report a molecular and cytogenetic investigation of a psu dic(Yp) chromosome identified in blood and ovarian tissue from a female with mosaic karyotype 45,X/46,X,+ psu dic(Yp). FISH analysis showed that the psu dic(Yp) has two copies of the short arm, two centromeres and two copies of the proximal long arm. PCR analysis also confirmed the presence of the SRY gene and the Y centromere, and also confirmed the deletion of the Y-heterochromatic region. Because of the possibility of a mutation, a fragment of 609 bp of the SRY gene was sequenced from independent PCR products. The analysis of the sequence indicated the presence of two different copies of the gene: one presented a point mutation, R59G, within the HMG-box; the other had a sequence identical to that already published. Both sequences were found at a proportion of 1:1. The absence of a 46,XY cell line suggests that the rearrangement took place during gametogenesis or during the first division after fertilization. Also, the existence of different sequences of the SRYgene in the same Y chromosome suggests that the formation of the dicentric took place prior to the mutation of the SRY gene. To our knowledge, this is the first time that a mutation has been described in codon 59 within the HMG- SRY box, and also the first case of a psu dic(Yp) chromosome that displays two different copies of the SRY gene.

The Role of <i>SRY</i> Mutations in the Etiology of Gonadal Dysgenesis in Patients with 45,X/46,XY Disorder of Sex Development and Variants

“…Mutations in SRY gene have also been identified in 5 further patients with Y chromosome mosaicism with the karyotypes 45,X/47,XYY (n = 1), 45,X/46,X,psu dic(Y) (pter→q11::q11→pter) (n = 1) and 45,X/46,XY (n = 3) [15,16,22]. All of them presented with female external genitalia, and in 4 patients, dysgenetic gonads were observed.…”

“…This mutation results in the substitution of an arginine by a glycine in the second codon within the DNA-binding HMG box domain. This Arg59 is strictly conserved among species suggesting that it could be important for the protein function [16]. …”

“…The potential involvement of mutations in SRY in abnormal testis determination in 45,X/46,X,der(Y) patients was reinforced by the description of SRY mutations in patients with TS harboring Y material [14,15,16]. …”

Sex Chromosome Mosaicism in the Gonads of DSD Patients: A Karyotype/Phenotype Correlation

“…Other associated factors such as mutations affecting the SRY gene or other genes involved in the testis-determining pathway could not be excluded in such cases [Fernandez et al, 2002;Alvarez-Nava et al, 2003;Canto et al, 2004]. Patient 3 exhibited an idic(Yq) abnormality in 36% of blood lymphocytes, associated with a 45,X cell line.…”

Turner Syndrome and Sex Chromosomal Mosaicism

“…A small marker chromosome was found in 28 of 40 G-banded metaphases from peripheral blood lymphocytes in mosaic karyotype with a 45,X cell line. The G-banding pattern exhibited a marker chromosome similar in size to a member of group F (chromosomes 19 and 20) but did not unequivocally suggest its genetic content (Figure 2) (Fernandez et al, 2002). When 559 metaphases were analyzed by FISH, the DYZ3 probe revealed, in 60% of the cells, a double hybridization signal in the marker chromosome (Figure 2).…”