No abstract

CHARGE syndrome and Kallmann syndrome (KS) are two distinct developmental disorders sharing overlapping features of impaired olfaction and hypogonadism. KS is a genetically heterogeneous disorder consisting of idiopathic hypogonadotropic hypogonadism (IHH) and anosmia, and is most commonly due to KAL1 or FGFR1 mutations. CHARGE syndrome, a multisystem autosomal-dominant disorder, is caused by CHD7 mutations. We hypothesized that CHD7 would be involved in the pathogenesis of IHH and KS (IHH/KS) without the CHARGE phenotype and that IHH/KS represents a milder allelic variant of CHARGE syndrome. Mutation screening of the 37 protein-coding exons of CHD7 was performed in 101 IHH/KS patients without a CHARGE phenotype. In an additional 96 IHH/KS patients, exons 6-10, encoding the conserved chromodomains, were sequenced. RT-PCR, SIFT, protein-structure analysis, and in situ hybridization were performed for additional supportive evidence. Seven heterozygous mutations, two splice and five missense, which were absent in > or = 180 controls, were identified in three sporadic KS and four sporadic normosmic IHH patients. Three mutations affect chromodomains critical for proper CHD7 function in chromatin remodeling and transcriptional regulation, whereas the other four affect conserved residues, suggesting that they are deleterious. CHD7's role is further corroborated by specific expression in IHH/KS-relevant tissues and appropriate developmental expression. Sporadic CHD7 mutations occur in 6% of IHH/KS patients. CHD7 represents the first identified chromatin-remodeling protein with a role in human puberty and the second gene to cause both normosmic IHH and KS in humans. Our findings indicate that both normosmic IHH and KS are mild allelic variants of CHARGE syndrome and are caused by CHD7 mutations.

By defining the chromosomal breakpoint of a balanced t(10;12) translocation from a subject with Kallmann syndrome and scanning genes in its vicinity in unrelated hypogonadal subjects, we have identified WDR11 as a gene involved in human puberty. We found six patients with a total of five different heterozygous WDR11 missense mutations, including three alterations (A435T, R448Q, and H690Q) in WD domains important for β propeller formation and protein-protein interaction. In addition, we discovered that WDR11 interacts with EMX1, a homeodomain transcription factor involved in the development of olfactory neurons, and that missense alterations reduce or abolish this interaction. Our findings suggest that impaired pubertal development in these patients results from a deficiency of productive WDR11 protein interaction.

The relationships between plasma gonadotropins, testicular gonadotropin receptors, and plasma testosterone were examined during neonatal life and throughout sexual maturation in the rat. The binding affinity of testicular LH receptors (2.4 X 10(10) M-1) was significantly higher than that of FSH receptors (2.1 X 10(9) M-1) at all stages of development. The concentration of FSH receptors in the testis reached a peak between 10-15 days of age, then fell to a constant level from 25-90 days. However, the testis content of FSH receptors increased continually with age and reached a plateau at day 60. Plasma FSH declined after birth to a nadir at 15 days, then rose rapidly to a peak at day 38, and fell to a plateau from day 50 through adult life. In contrast to the rapidly changing profile of plasma FSH during early maturation, alterations in plasma LH were less marked throughout development. Although a progressive rise in plasma LH concentration was observed between days 36-51, the simultaneous changes in testicular LH receptors and plasma testosterone were much more prominent. Testicular LH receptors showed a continuous increase in concentration and total number with advancing age and testis growth. The major rise in LH receptor concentration occurred between 15-38 days age, at the same time as the rise in plasma FSH concentration and the phase of rapid testicular growth. Plasma testosterone fell during the 8th-24th days after birth, then rose rapidly between days 35-55. The pubertal rise in plasma testosterone occurred about 15 days after testicular LH receptors began to increase and was coincident with the continuing rise in LH receptor content from day 35 until day 55 and with the progressive increase in plasma LH during this period. These observations have demonstrated that the early development of testicular FSH receptors in followed by a prominent rise in plasma FSH, with concomitant increases in testicular growth and LH receptor concentration. The resulting increase in gonadal sensitivity to LH could be responsible for the marked increase in secretion of testosterone which occurs during puberty in the presence of a relatively small change in the circulating LH concentration. The sequence of changes observed in gonadotropins and their testicular receptors is consistent with the view that FSH-induced testicular sensitivity to LH is an important factor in sexual maturation in the male rat.