In 'patient 213' (patient 4 in the report of Berkovitz et al., 1991), a phenotypic female with complete gonadal dysgenesis and a 46,XY karyotype (SRXY1; 400044), Hawkins et al. (1992) identified a C-G transversion at nucleotide 680, causing an isoleucine-to-methionine amino acid substitution within the HMG box. The father and brother of patient 213 also carried the mutation, which was not found in 78 ethnically matched unrelated males. The authors noted that in vitro studies by Harley et al. (1992) demonstrated that the I90M mutant had reduced DNA-binding activity.
Dork et al. (1998) observed this mutation in a patient unrelated to that reported by Hawkins et al. (1992). None of the previously reviewed mutations had been observed in more than a single family. In 3 cases, however, fertile fathers were found to share the same SRY mutation with their sex-reversed daughters (Berta et al., 1990; Jager et al., 1992; Vilain et al., 1992). In the absence of mosaicism, there are plausible explanations for these familiar variants. The variant could fortuitously occur in a family segregating for a different sex-reversing gene, or the variant may predispose toward sex reversal and cause a differentiation effect only in association with other genetic or environmental factors. In the case reported by Hawkins et al. (1992), I90M was likewise associated with complete gonadal dysgenesis in the proband but was also present in normal relatives of the patient, including the father. Thus, Dork et al. (1998) concluded that this appears to be an instance of a Y-linked inherited disorder with incomplete penetrance and suggested that identification of unrelated individuals carrying the I90M mutation may help to elucidate the mechanism.
Maier et al. (2003) reported a 46,XY true hermaphrodite (see 400044) who had the I90M mutation in the SRY gene. The father, 3 uncles, and an older brother carried the identical mutation without phenotypic effects. Maier et al. (2003) concluded that the mutated protein retained enough activity to allow normal development in some individuals.
