Sex-determining gene(s) on distal 9p: clinical and molecular studies in six cases.
We report on clinical and molecular findings in five karyotypic males (cases 1-5) and one karyotypic female (case 6) with distal 9p monosomy. Cases 1-3 and 6 had female external genitalia, case 4 showed ambiguous external genitalia, and case 5 exhibited male external genitalia with left cryptorchidism and right intrascrotal testis. Gonadal explorations at gonadectomy in cases 3 and 4 revealed that case 3 had left streak gonad and right agonadism, and case 4 had bilateral hypoplastic testes. Endocrine studies in cases 1-4 and 6 showed that cases 1, 3, and 6 had definite primary hypogonadism, with basal FSH levels of 54, 39, and 41 IU/L, respectively, whereas case 2 with severe malnutrition was unremarkable for the baseline values, and case 4 had fairly good testicular function. Fluorescence in situ hybridization and microsatellite analyses demonstrated that all cases had hemizygosity of the 9p sex-determining region distal to D9S1779, with loss of the candidate sex-determining genes DMRT1 and DMRT2 from the abnormal chromosome 9. Sequence analysis in cases 1-4 and 6 showed that they had normal sequences of each exon of DMRT1 and the DM domain of DMRT2 on the normal chromosome 9, and that cases 1-4 had normal SRY sequence. The results provide further support for the presence of a sex-determining gene(s) on distal 9p and favor the possibility of DMRT1 and/or DMRT2 being the sex-determining gene(s). Furthermore, as hemizygosity of the 9p sex-determining region was associated with a wide spectrum of gonadogenesis from agonadism to testis formation in karyotypic males and with primary hypogonadism regardless of karyotypic sex, it is inferred that haploinsufficiency of the 9p sex-determining gene(s) primarily hinders the formation of indifferent gonad, leading to various degrees of defective testis formation in karyotypic males and impaired ovary formation in karyotypic females.
Muroya
K
K
Department of Pediatrics, Keio University School of Medicine, Tokyo, Japan.
Okuyama
T
T
Goishi
K
K
Ogiso
Y
Y
Fukuda
S
S
Kameyama
J
J
Sato
H
H
Suzuki
Y
Y
Terasaki
H
H
Gomyo
H
H
Wakui
K
K
Fukushima
Y
Y
Ogata
T
T
D000328:Adult; D002675:Child, Preschool; D002899:Chromosomes, Human, Pair 9 / Q000235:genetics*; D005260:Female; D005835:Genitalia / Q000473:pathology; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D007223:Infant; D008607:Intellectual Disability / Q000235:genetics; D007621:Karyotyping; D008297:Male; D018895:Microsatellite Repeats; D009006:Monosomy / Q000235:genetics / Q000503:physiopathology*; D012150:Polymorphism, Restriction Fragment Length; D020133:Reverse Transcriptase Polymerase Chain Reaction; D019849:Sex Determination Processes