The C-terminal part of the desert hedgehog protein precursor displays an autoproteolysis and a cholesterol transferase activity (By similarity). Both activities result in the cleavage of the full-length protein into two parts (N-product and C-product) followed by the covalent attachment of a cholesterol moiety to the C-terminal of the newly generated N-product (DHH-N) (By similarity). Both activities occur in the endoplasmic reticulum (By similarity). Once cleaved, the C-product is degraded in t

Cell membraneEndoplasmic reticulum membraneGolgi apparatus membraneSecreted

46,XY gonadal dysgenesis with minifascicular neuropathy

An autosomal recessive disorder characterized by gonadal dysgenesis associated with polyneuropathy. Genital anomalies include the presence of a testis on one side and a streak or an absent gonad at the other, persistence of Muellerian duct structures, and a variable degree of genital ambiguity.

Cytosolic aldo-keto reductase that catalyzes NADPH-dependent reduction of ketosteroids to hydroxysteroids. Displays broad substrate specificity with distinct positional and stereochemistry, primarily generating 3alpha/beta-, 17beta- and 20alpha-hydroxysteroids (PubMed:10634139, PubMed:10998348, PubMed:11158055, PubMed:14672942, PubMed:1530633, PubMed:12604236, PubMed:19218247, PubMed:21802064, PubMed:7650035). Required for male sex determination as a component of the 'backdoor' androgen biosynth

Cytoplasm, cytosol

46,XY sex reversal 8

A disorder of sex development. Affected individuals have a 46,XY karyotype but present as phenotypically normal females.

Cytosolic aldo-keto reductase that catalyzes NADPH-dependent reduction of ketosteroids to hydroxysteroids. Displays broad substrate specificity with distinct positional and stereochemistry, primarily generating 3alpha-hydroxysteroids, but also 3beta-, 17beta- and 20alpha-hydroxysteroids (PubMed:8920937, PubMed:9716498, PubMed:10998348, PubMed:12416991, PubMed:11995921, PubMed:12604236, PubMed:14672942, PubMed:19218247, PubMed:21802064, PubMed:11514561, PubMed:15929998, PubMed:17034817, PubMed:17

Cytoplasm, cytosol

46,XY sex reversal 8

A disorder of sex development. Affected individuals have a 46,XY karyotype but present as phenotypically normal females.

Transcription regulator that plays a central role in heart morphogenesis and development of coronary vessels from epicardium, by regulating genes that are essential during cardiogenesis. Essential cofactor that acts via the formation of a heterodimer with transcription factors of the GATA family GATA4, GATA5 and GATA6. Such heterodimer can both activate or repress transcriptional activity, depending on the cell and promoter context. Also required in gonadal differentiation, possibly be regulatin

Nucleus

Tetralogy of Fallot

A congenital heart anomaly which consists of pulmonary stenosis, ventricular septal defect, dextroposition of the aorta (aorta is on the right side instead of the left) and hypertrophy of the right ventricle. In this condition, blood from both ventricles (oxygen-rich and oxygen-poor) is pumped into the body often causing cyanosis.

Transcriptional activator. Essential for sexual differentiation and formation of the primary steroidogenic tissues (PubMed:27378692). Binds to the Ad4 site found in the promoter region of steroidogenic P450 genes such as CYP11A, CYP11B and CYP21B. Also regulates the AMH/Muellerian inhibiting substance gene as well as the AHCH and STAR genes. 5'-YCAAGGYC-3' and 5'-RRAGGTCA-3' are the consensus sequences for the recognition by NR5A1 (PubMed:27378692). The SFPQ-NONO-NR5A1 complex binds to the CYP17

Nucleus

46,XY sex reversal 3

A condition characterized by male-to-female sex reversal in the presence of a normal 46,XY karyotype.

Component of a protein kinase signal transduction cascade (PubMed:9808624). Activates the ERK and JNK kinase pathways by phosphorylation of MAP2K1 and MAP2K4 (PubMed:9808624). May phosphorylate the MAPK8/JNK1 kinase (PubMed:17761173). Activates CHUK and IKBKB, the central protein kinases of the NF-kappa-B pathway (PubMed:9808624)

46,XY sex reversal 6

A disorder of sex development. Affected individuals have a 46,XY karyotype but present as phenotypically normal females.

ATP-binding RNA helicase that plays a role in maturation of the small ribosomal subunit in ribosome biogenesis (PubMed:30582406). Required for the release of the U3 snoRNP from pre-ribosomal particles (PubMed:30582406). Part of the small subunit (SSU) processome, first precursor of the small eukaryotic ribosomal subunit. During the assembly of the SSU processome in the nucleolus, many ribosome biogenesis factors, an RNA chaperone and ribosomal proteins associate with the nascent pre-rRNA and wor

Nucleus, nucleolusCytoplasmNucleus membrane

Neurodevelopmental disorder with brain anomalies and with or without vertebral or cardiac anomalies

An autosomal recessive neurodevelopmental disorder characterized by severe developmental delay, impaired intellectual development, hypotonia, brain anomalies including cortical volume loss, corpus callosum dysgenesis and cerebellar hypoplasia, and variable dysmorphic features. Patients may have platyspondyly, scoliosis, and cardiac anomalies.

Component of a Polycomb group (PcG) multiprotein PRC1-like complex, a complex class required to maintain the transcriptionally repressive state of many genes, including Hox genes, throughout development (PubMed:21282530). PcG PRC1 complex acts via chromatin remodeling and modification of histones; it mediates monoubiquitination of histone H2A 'Lys-119', rendering chromatin heritably changed in its expressibility (PubMed:21282530). Binds to histone H3 trimethylated at 'Lys-9' (H3K9me3) or at 'Lys

NucleusChromosome

46,XY sex reversal 5

A disorder of sex development. Affected individuals have a 46,XY karyotype but present as phenotypically normal females.

Transcription factor that plays an important role in cellular development and cell survival (PubMed:7862533). Recognizes and binds to the DNA sequence 5'-GCG(T/G)GGGCG-3' (PubMed:17716689, PubMed:25258363, PubMed:7862533). Regulates the expression of numerous target genes, including EPO. Plays an essential role for development of the urogenital system. It has a tumor suppressor as well as an oncogenic role in tumor formation. Function may be isoform-specific: isoforms lacking the KTS motif may a

NucleusNucleus, nucleolusCytoplasmNucleus speckleNucleus, nucleoplasm

Frasier syndrome

Characterized by a slowly progressing nephropathy leading to renal failure in adolescence or early adulthood, male pseudohermaphroditism, and no Wilms tumor. As for histological findings of the kidneys, focal glomerular sclerosis is often observed. There is phenotypic overlap with Denys-Drash syndrome. Inheritance is autosomal dominant.

Transcription factor that plays a key role in male sex determination and differentiation by controlling testis development and male germ cell proliferation. Plays a central role in spermatogonia by inhibiting meiosis in undifferentiated spermatogonia and promoting mitosis, leading to spermatogonial development and allowing abundant and continuous production of sperm. Acts both as a transcription repressor and activator: prevents meiosis by restricting retinoic acid (RA)-dependent transcription a

Nucleus

Testicular germ cell tumor

A common malignancy in males representing 95% of all testicular neoplasms. TGCTs have various pathologic subtypes including: unclassified intratubular germ cell neoplasia, seminoma (including cases with syncytiotrophoblastic cells), spermatocytic seminoma, embryonal carcinoma, yolk sac tumor, choriocarcinoma, and teratoma.

Transcription factor that plays a key role in chondrocytes differentiation and skeletal development (PubMed:24038782). Specifically binds the 5'-ACAAAG-3' DNA motif present in enhancers and super-enhancers and promotes expression of genes important for chondrogenesis, including cartilage matrix protein-coding genes COL2A1, COL4A2, COL9A1, COL11A2 and ACAN, SOX5 and SOX6 (PubMed:8640233). Also binds to some promoter regions (By similarity). Plays a central role in successive steps of chondrocyte

Nucleus

Campomelic dysplasia

A rare, often lethal, osteochondrodysplasia characterized by congenital bowing and angulation of long bones. Other skeletal defects include unusually small scapula, deformed pelvis and spine, and a missing pair of ribs. Craniofacial and ear defects are common. Most patients die soon after birth due to respiratory distress which has been attributed to hypoplasia of the tracheobronchial cartilage and small thoracic cage. Up to two-thirds of affected XY individuals have genital defects or may develop as phenotypic females.

Transcriptional regulator that controls a genetic switch in male development (PubMed:11563911). It is necessary and sufficient for initiating male sex determination by directing the development of supporting cell precursors (pre-Sertoli cells) as Sertoli rather than granulosa cells (PubMed:16414182, PubMed:16996051). Involved in different aspects of gene regulation including promoter activation or repression (PubMed:9525897). Binds to the DNA consensus sequence 5'-[AT]AACAA[AT]-3' (PubMed:115639

Nucleus speckleCytoplasmNucleus

46,XY sex reversal 1

A condition characterized by male-to-female sex reversal in the presence of a normal 46,XY karyotype. Patients manifest rapid and early degeneration of their gonads, which are present in the adult as 'streak gonads', consisting mainly of fibrous tissue and variable amounts of ovarian stroma. As a result these patients do not develop secondary sexual characteristics at puberty. The external genitalia in these subjects are completely female, and Muellerian structures are normal.

Nuclear receptor that lacks a DNA-binding domain and acts as a corepressor that inhibits the transcriptional activity of other nuclear receptors through heterodimeric interactions (PubMed:12482977, PubMed:32433991). Component of a cascade required for the development of the hypothalamic-pituitary-adrenal-gonadal axis (PubMed:7990953, PubMed:8675564). May also have a role in the development of the embryo and in the maintenance of embryonic stem cell pluripotency (By similarity)

NucleusCytoplasm

Adrenal hypoplasia, congenital

A disorder of adrenal gland development characterized by absence of the permanent zone of the adrenal cortex, structural disorganization of the adrenal glands, adrenal insufficiency and profound hormonal deficiencies. AHC patients manifest primary adrenal failure usually in early infancy, and hypogonadotropic hypogonadism leading to absent or incomplete sexual maturation. AHC can be inherited in an X-linked or autosomal recessive pattern.