Double Proton Tautomerism via Intra- or Intermolecular Pathways? The Case of Tetramethyl Reductic Acid Studied by Dynamic NMR: Hydrogen Bond Association, Solvent and Kinetic H/D Isotope Effects.

Using dynamic liquid-state NMR spectroscopy a degenerate double proton tautomerism was detected in tetramethyl reductic acid (TMRA) dissolved in toluene- and in CDCl. Similar to vitamin C, TMRA belongs to the class of reductones of biologically important compounds. The tautomerism involves an intramolecular HH transfer that interconverts the peripheric and the central positions of the two OH groups.

Four Novel NR5A1 Mutations in 46,XY Gonadal Dysgenesis Patients Including Frameshift Mutations with Altered Subcellular SF-1 Localization.

46,XY gonadal dysgenesis (46,XY GD) is a disorder of sexual development caused by mutations in genes involved in early gonadal development (bipotential gonads) and testis differentiation. In 46,XY GD individuals, mutations of the SRY gene are detected most frequently, followed by mutations in the NR5A1 (SF-1) gene, but in a lot of cases, the underlying molecular mechanism remains elusive. In this study, we retrospectively performed sequence analyses of the NR5A1 (SF-1) gene in 84 patients with complete, partial, and syndromic forms of 46,XY GD.

A mutation creating an upstream initiation codon in the 5' UTR causes acampomelic campomelic dysplasia.

Background: Campomelic dysplasia (CD) is a semilethal developmental disorder caused by mutations in and around . CD is characterized by multiple skeletal malformations including bending (campomelia) of long bones. Surviving patients frequently have the acampomelic form of CD (ACD).

Sox9 and Sox8 protect the adult testis from male-to-female genetic reprogramming and complete degeneration.

The new concept of mammalian sex maintenance establishes that particular key genes must remain active in the differentiated gonads to avoid genetic sex reprogramming, as described in adult ovaries after Foxl2 ablation. Dmrt1 plays a similar role in postnatal testes, but the mechanism of adult testis maintenance remains mostly unknown. Sox9 and Sox8 are required for postnatal male fertility, but their role in the adult testis has not been investigated.

FGFR2 mutation in 46,XY sex reversal with craniosynostosis.

Patients with 46,XY gonadal dysgenesis (GD) exhibit genital anomalies, which range from hypospadias to complete male-to-female sex reversal. However, a molecular diagnosis is made in only 30% of cases. Heterozygous mutations in the human FGFR2 gene cause various craniosynostosis syndromes including Crouzon and Pfeiffer, but testicular defects were not reported.

A case of campomelic dysplasia in whom a new mutation was found in the SOX9 gene.

Campomelic dysplasia (CD, OMIM #114290) is a rare autosomal dominant disease characterized with bending and shortness in the long bones of the lower extremities, typical facial features, hypoplastic scapula, costa defect, narrow thorax and pes equinovarus. Campomelic dysplasia occurs with heterozygous mutations in the SOX9 gene in the 17q24 chromosome. The main findings of our four-day old patient included typical facial features, risomelic extremity shortness, angular bending in the long bones of bilateral lower extremities and pes equinovarus.

Copy number variation of two separate regulatory regions upstream of SOX9 causes isolated 46,XY or 46,XX disorder of sex development.

Background: SOX9 mutations cause the skeletal malformation syndrome campomelic dysplasia in combination with XY sex reversal. Studies in mice indicate that SOX9 acts as a testis-inducing transcription factor downstream of SRY, triggering Sertoli cell and testis differentiation. An SRY-dependent testis-specific enhancer for Sox9 has been identified only in mice.

Scx+/Sox9+ progenitors contribute to the establishment of the junction between cartilage and tendon/ligament.

SRY-box containing gene 9 (Sox9) and scleraxis (Scx) regulate cartilage and tendon formation, respectively. Here we report that murine Scx(+)/Sox9(+) progenitors differentiate into chondrocytes and tenocytes/ligamentocytes to form the junction between cartilage and tendon/ligament. Sox9 lineage tracing in the Scx(+) domain revealed that Scx(+) progenitors can be subdivided into two distinct populations with regard to their Sox9 expression history: Scx(+)/Sox9(+) and Scx(+)/Sox9(-) progenitors.

Acampomelic form of campomelic dysplasia with SOX9 missense mutation.

Campomelic dysplasia is a skeletal dysplasia characterized by flat face, Pierre Robin sequence, shortening and bowing of long bones and club feet. The authors describe a case of "acampomelic" campomelic dysplasia that differs from classical campomelic dysplasia by the absence of bone bowing. This condition is among the most common skeletal dysplasias but is often misdiagnosed in the absence of overt campomelia.

Tyrosinemia Type III detected via neonatal screening: management and outcome.

Tyrosinemia Type III is caused by the deficiency of 4-hydroxyphenylpyruvate dioxygenase (4-HPPD), an enzyme involved in the catabolic pathway of tyrosine. To our knowledge, only a few patients presenting with this disease have been described in the literature, and the clinical phenotype remains variable and unclear. We report the case of a boy with tyrosinemia Type III detected using neonatal screening, who is homozygous for the splice donor mutation IVS11+1G>A in intron 11 of the HPD gene.

Genes promoting and disturbing testis development.

Mammals have an XX/XY sex chromosomal sex determination system in which males represent the heterogametic sex. The Y-linked gene, SRY, determines sex by inducing the undifferentiated, bipotential gonads to differentiate as testes, which produce androgens and promote in this way the development of a male phenotype. Thus, in mammals, sex determination can be equated to testis determination, which involves several important cell processes, including Sertoli cell differentiation, mesonephric cell migration, testis cord formation, testis-specific vascularization, and myoid and Leydig cell differentiation.

Sox9 and Sox8 are required for basal lamina integrity of testis cords and for suppression of FOXL2 during embryonic testis development in mice.

The sex-determining gene Sry and its target gene Sox9 initiate the early steps of testis development in mammals. Of the related Sox genes Sox8, Sox9, and Sox10, all expressed during Sertoli cell differentiation, only inactivation of Sox9 before the sex determination stage at Embryonic Day 11.5 (E11.

L-Sox5 and Sox6 proteins enhance chondrogenic miR-140 microRNA expression by strengthening dimeric Sox9 activity.

Sox9 plays a critical role in early chondrocyte initiation and promotion as well as repression of later maturation. Fellow Sox family members L-Sox5 and Sox6 also function as regulators of cartilage development by boosting Sox9 activation of chondrocyte-specific genes such as Col2a1 and Agc1; however, the regulatory mechanism and other target genes are largely unknown. MicroRNAs are a class of short, non-coding RNAs that act as negative regulators of gene expression by promoting target mRNA degradation and/or repressing translation.

A large TAT deletion in a tyrosinaemia type II patient.

A girl, born to unrelated Spanish parents, presented at 6 months of age with photophobia, keratitis, palmar hyperkeratosis and high plasma tyrosine levels, indicative of tyrosinaemia type II. Analysis of the tyrosine aminotransferase (TAT) gene revealed a paternally inherited frameshift mutation c.1213delCinsAG at codon 405 causing a premature stop codon, and a maternally inherited deletion of 193kb encompassing the complete TAT gene and three neighbouring genes.

Profiling spermatogenic failure in adult testes bearing Sox9-deficient Sertoli cells identifies genes involved in feminization, inflammation and stress.

Background: Sox9 (Sry box containing gene 9) is a DNA-binding transcription factor involved in chondrocyte development and sex determination. The protein's absence in testicular Sertoli nurse cells has been shown to disrupt testicular function in adults but little is known at the genome-wide level about molecular events concomitant with testicular break-down.

Methods: To determine the genome-wide effect on mRNA concentrations triggered by the absence of Sox9 in Sertoli cells we analysed adult testicular tissue from wild-type versus mutant mice with high-density oligonucleotide microarrays and integrated the output of this experiment with regulatory motif predictions and protein-protein network data.

Hydroureternephrosis due to loss of Sox9-regulated smooth muscle cell differentiation of the ureteric mesenchyme.

Congenital ureter anomalies, including hydroureter, affect up to 1% of the newborn children. Despite the prevalence of these developmental abnormalities in young children, the underlying molecular causes are only poorly understood. Here, we show that the high mobility group domain transcription factor Sox9 plays an important role in ureter development in the mouse.

Mutations of the SRY-responsive enhancer of SOX9 are uncommon in XY gonadal dysgenesis.

During mouse sex determination, SRY upregulates the core testis-specific enhancer of Sox9, TESCO. Mutations in human SRY are found in one third of cases with XY pure gonadal dysgenesis (XY GD; Swyer syndrome), while two thirds remain unexplained. Heterozygous SOX9 mutations can cause XY GD in association with the skeletal malformation syndrome campomelic dysplasia.

Dicer is required for Sertoli cell function and survival.

Dicer is a key enzyme that processes microRNA precursors into their mature form, enabling them to regulate gene expression. Dicer null mutants die before gastrulation. To study Dicer function in testis development, we crossed mice carrying a conditional Dicer allele with an AMH-Cre transgenic line, thereby inactivating Dicer in Sertoli cells around embryonic day 14.

SOX E genes: SOX9 and SOX8 in mammalian testis development.

The group E SOX proteins consist of SOX8, SOX9 and SOX10. These transcription factors contain, besides a DNA-binding HMG domain and a transactivation domain, a DNA-dependent dimerization domain, unique among SOX proteins. Among these three SOX E proteins, which are all expressed during mammalian testis development, SOX9 stands out in importance.

The PGD2 pathway, independently of FGF9, amplifies SOX9 activity in Sertoli cells during male sexual differentiation.

Activation by the Y-encoded testis determining factor SRY and maintenance of expression of the Sox9 gene encoding the central transcription factor of Sertoli cell differentiation are key events in the mammalian sexual differentiation program. In the mouse XY gonad, SOX9 upregulates Fgf9, which initiates a Sox9/Fgf9 feedforward loop, and Sox9 expression is stimulated by the prostaglandin D2 (PGD2) producing lipocalin prostaglandin D synthase (L-PGDS, or PTDGS) enzyme, which accelerates commitment to the male pathway. In an attempt to decipher the genetic relationships between Sox9 and the L-Pgds/PGD2 pathway during mouse testicular organogenesis, we found that ablation of Sox9 at the onset or during the time window of expression in embryonic Sertoli cells abolished L-Pgds transcription.

Alu-Alu recombination underlies the vast majority of large VHL germline deletions: Molecular characterization and genotype-phenotype correlations in VHL patients.

Von Hippel-Lindau disease (VHL) is an autosomal dominant cancer syndrome. Affected individuals are predisposed to multiple tumors, primarily of the central nervous system (CNS), eyes, adrenals, and kidneys. The VHL tumor suppressor gene on chromosome 3p26-25 is partially or completely deleted in 20 to 30% of families with VHL.

Testis cord differentiation after the sex determination stage is independent of Sox9 but fails in the combined absence of Sox9 and Sox8.

Sox9 and Sox8 are transcription factors expressed in embryonic and postnatal Sertoli cells of the mouse testis. Sox9 inactivation prior to the sex determination stage leads to complete XY sex reversal. In contrast, there is normal embryonic testis development in Sox8 mutants which are initially fertile, but later develop progressive seminiferous tubule failure and infertility.