Novel DMRT1 3'UTR+11insT mutation associated to XY partial gonadal dysgenesis

Abstract

The Y-chromosome-located SRY gene encodes a small testis-specific protein containing a DNA-binding motif known as the HMG (high mobility group) box. However, mutations in SRY are not frequent especially in cases of 46,XY partial gonadal dysgenesis. Several sex-determining genes direct the fate of the bipotential gonad to either testis or ovary. In addition, heterozygous small deletions in 9p can cause complete and partial XY gonadal dysgenesis without other symptoms. Human DMRT1 gene, which is located at 9p24.3, is expressed in testis and ovary and has been considered, among others, a candidate autosomal gene responsible for gonadal dysgenesis. In this report we describe a nucleotide insertion in DMRT1 3'UTR in a patient of XY partial gonadal dygenesis. The 3'UTR+11insT is located within a conserved motif important for mRNA stabilization.

Absence of inactivating mutations and deletions in the DMRT1 and FGF9 genes in a large cohort of 46,XY patients with gonadal dysgenesis

“…The c.*11_*12insT variant, previously identified in a 46,XY partial GD patient by Mello et al [23], was found in this cohort of patients (9 of 33 patients) but also in the control subjects (12 of 89 individuals). Statistical analysis indicated that this variant was not significantly more prevalent in the patient group (Table 3).…”

Partial deletion of DMRT1 causes 46,XY ovotesticular disorder of sexual development

“…Recently, an insertion near the stop codon in the 3 0 -UTR of DMRT1 in a patient with XY gonadal dysgenesis was detected, potentially disturbing gonadspecific stabilization of the corresponding mRNA (21). Furthermore, in two sisters with XY gonadal dysgenesis, Calvari et al (27) identified a small deletion in 9p, affecting a suspected regulatory region of DMRT1.…”

“…Furthermore, it is related to sex-determining genes in nematodes and insects (19). Mutational analysis in all three genes resulted in only two potential pathogenic mutations of DMRT1 (20,21). Recently, we showed that deletions of only DMRT1 can cause XY gonadal dysgenesis (22).…”

Gender Development in 46,XY DSD: Influences of Chromosomes, Hormones, and Interactions with Parents and Healthcare Professionals

“…Similar to Swyer syndrome, partial gonadal dysgenesis can result from mutations of the SRY gene [79]. Additionally, dosage imbalances and mutations of DAX1 [80], DMRT1 [81], and MAP3K1 [20] have been documented. The genital phenotype of affected newborns can resemble that of newborn with ambiguous genitalia due to PAIS, 5 α -RD2, or 17 β HSD-3 deficiencies; however, serum MIS levels effectively distinguish between these different causes of 46,XY DSD if this peptide hormone is measured at appropriate times [82].…”