Sex-Determining Gene(s) on Distal 9p: Clinical and Molecular Studies in Six Cases*

Abstract

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.

Clinical Assessment and Mutation Analysis of Kallmann Syndrome 1 (KAL1) and Fibroblast Growth Factor Receptor 1 (FGFR1, orKAL2) in Five Families and 18 Sporadic Patients

“…Endocrine status was examined by a GnRH test (100 g/m 2 bolus iv; blood sampling at 0, 30, 60, 90, and 120 min) for patients of both sexes and by a human chorionic gonadotropin (hCG) test (3000 IU/m 2 ⅐dose im for 3 consecutive days; blood sampling on d 1-4) for male patients. The hormone levels were assessed by the age-, sex-, and pubertal-tempo matched Japanese reference data (25)(26)(27).…”

Array-CGH analysis in patients with syndromic and non-syndromic XY gonadal dysgenesis: evaluation of array CGH as diagnostic tool and search for new candidate loci

“…Distal monosomy of 9p including DMRT1 -3 genes has been described in some XY-GD patients, and a case with bilateral ovotestes has also been reported (Muroya et al, 2000;Õ unap et al, 2004). Among the three DMRT genes, DMRT1 is the strongest candidate gene.…”

A brother and sister with the same karyotype: Case report of two siblings with partial 3p duplication and partial 9p deletion and sex reversal

“…This region is separate from the 9p deletion syndrome critical region (9p22.3‐9p23) 15,16 . The DMRT genes ( DMRT1 , DMRT2 , and DMRT3 ) located at 9p24.3 are considered as gene candidates for gonadal dysgenesis 17 . These genes encode for proteins with a DM (doublesex/MAB‐3) domain, a zinc‐finger‐like DNA binding, and are involved in downstream pathways of sex determination 13 .…”

“…15,16 The DMRT genes (DMRT1, DMRT2, and DMRT3) located at 9p24.3 are considered as gene candidates for gonadal dysgenesis. 17 These genes encode for proteins with a DM (doublesex/ MAB-3) domain, a zinc-finger-like DNA binding, and are involved in downstream pathways of sex determination. 13 In mice, Dmrt1 is expressed in both germ cells and Sertoli cells of the testis, and has been shown to be essential to maintain testis determination.…”