XX female gonadal dysgenesis (XX-GD) is a rare, genetically heterogeneous disorder characterized by lack of spontaneous pubertal development, primary amenorrhea, uterine hypoplasia, and hypergonadotropic hypogonadism as a result of streak gonads. Most cases are unexplained but thought to be autosomal recessive. We elucidated the genetic basis of XX-GD in a highly consanguineous Palestinian family by using homozygosity mapping and candidate-gene and whole-exome sequencing. Affected females were homozygous for a 3 bp deletion (NM_016556.2, c.600_602del) in the PSMC3IP gene, leading to deletion of a glutamic acid residue (p.Glu201del) in the highly conserved C-terminal acidic domain. Proteasome 26S subunit, ATPase, 3-Interacting Protein (PSMC3IP)/Tat Binding Protein Interacting Protein (TBPIP) is a nuclear, tissue-specific protein with multiple functions. It is critical for meiotic recombination as indicated by the known role of its yeast ortholog, Hop2. Through the C terminus (not present in yeast), PSMC3IP also coactivates ligand-driven transcription mediated by estrogen, androgen, glucocorticoid, progesterone, and thyroid nuclear receptors. In cell lines, the p.Glu201del mutation abolished PSMC3IP activation of estrogen-driven transcription. Impaired estrogenic signaling can lead to ovarian dysgenesis both by affecting the size of the follicular pool created during fetal development and by failing to counteract follicular atresia during puberty. PSMC3IP joins previous genes known to be mutated in XX-GD, the FSH receptor, and BMP15, highlighting the importance of hormonal signaling in ovarian development and maintenance and suggesting a common pathway perturbed in isolated XX-GD. By analogy to other XX-GD genes, PSMC3IP is also a candidate gene for premature ovarian failure, and its role in folliculogenesis should be further investigated.

OBJECTIVE— Congenital hyperinsulinism, usually associated with severe neonatal hypoglycemia, may progress to diabetes, typically during the 4th decade of life in nonpancreatectomized patients. We aimed to genotype the ATP-sensitive K + channel in a 10.5-year-old girl presenting with overt diabetes following hyperinsulinism in infancy. RESEARCH DESIGN AND METHODS— A female aged 10.5 years presented with new-onset, antibody-negative diabetes (A1C 10.6%). She was born large for gestational age (5 kg) to a nondiabetic mother and developed frequent hypoglycemic episodes, which persisted until age 3 years and responded initially to intravenous glucose and later to oral sweets. Currently, she is fully pubertal and obese (BMI 30.2 kg/m 2 ), with a partially controlled convulsive disorder (since age 1 year) and poor school performance. Glucose levels were >11.1 mmol/l throughout 72 h of continuous glucose monitoring, with low insulin secretion during intravenous glucose tolerance testing. KCNJ11 and ABCC8 mutation analysis was performed, and the mutation identified was characterized in COSm6 cells. RESULTS— A novel, de novo heterozygous ABCC8 sulfonylurea receptor (SUR)1 mutation (R370S) was identified in the patient's DNA but not in that of either parent. Cotransfection of Kir6.2 and mutant SUR1 demonstrate that the mutated protein is expressed efficiently at the cell surface but fails to respond to MgADP, resulting in minimal channel activity. Interestingly, the heterozygous channel (WT:R370S) responded well to glibenclamide, a finding that lead to the successful initiation of sulfonylurea therapy. CONCLUSIONS— This new ABCC8 mutation is associated with neonatal hyperinsulinism progressing within 10 years to insulinopenic diabetes. Consistent with in vitro findings, the patient responded to sulfonylurea treatment. The mechanism causing the relatively rapid loss in β-cell function is not clear, but it may involve mutation-induced increased β-cell apoptosis related to increased metabolic demand.

NAF-1 deficiency leads to mitochondrial labile iron accumulation and oxidative stress, which may contribute to β-cell dysfunction in T2-WFS. Treatment with GLP-1-RA and/or iron chelation improves mitochondrial function and restores β-cell function. Treatment with GLP-1-RA, probably aided by iron chelation, should be considered in WFS and other forms of diabetes associated with iron dysregulation.

The transcription factor steroidogenic factor 1 (SF-1; also known as NR5A1) is a crucial mediator of both steroidogenic and nonsteroidogenic tissue differentiation. Mutations within SF1 underlie different disorders of sexual development (DSD), including sex reversal, spermatogenic failure, ovarian insufficiency, and adrenocortical deficiency. Here, we identified a recessive mutation within SF1 that resulted in a substitution of arginine to glutamine at codon 103 (R103Q) in a child with both severe 46,XY-DSD and asplenia. The R103Q mutation decreased SF-1 transactivation of TLX1, a transcription factor that has been shown to be essential for murine spleen development. Additionally, the SF1 R103Q mutation impaired activation of steroidogenic genes, without affecting synergistic SF-1 and sex-determining region Y (SRY) coactivation of the testis development gene SOX9. Together, our data provide evidence that SF-1 is required for spleen development in humans via transactivation of TLX1 and that mutations that only impair steroidogenesis, without altering the SF1/SRY transactivation of SOX9, can lead to 46,XY-DSD.