Paired-like homeobox 2b (PHOX2B), also known as neuroblastoma Phox (NBPhox), is a protein that in humans is encoded by the PHOX2B gene located on chromosome 4. [5]
It codes for a homeodomain transcription factor. It is expressed exclusively in the nervous system, in most neurons that control the viscera (cardiovascular, digestive and respiratory systems). It is also required for their differentiation.
Essential for the differentiation and survival of sympathetic neurons and chromaffin cells, the transcription factor PHOX2B is highly specific for the peripheral autonomic nervous system. Neuroblasts are derived from sympathoadrenal lineage neural crest cells and therefore require and constitutively express PHOX2B. PHOX2B immunohistochemical staining, as a marker of neural crest derivation, has been shown to be sensitive and specific for undifferentiated neuroblastoma, enabling identification where other markers fail to recognize neuroblastoma among various different small round blue cell tumors of childhood. [6] [7] [8] [9]
The diagnostic utility of PHOX2B staining extends to later stages of differentiation. Its strength and specificity can detect the small foci of neuroblastic tumors metastatic to the bone marrow, an identification critical for determining disease staging. PHOX2B staining also overcomes frequent obstacles to neuroblastoma detection in post-treatment samples, which frequently exhibit dense fibrosis, prominent inflammatory infiltrates, and/or diffuse calcification. [10]
Mutations in human PHOX2B cause a rare disease of the visceral nervous system (dysautonomia): congenital central hypoventilation syndrome (associated with respiratory arrests during sleep and, occasionally, wakefulness), Hirschsprung's disease (partial agenesis of the enteric nervous system), ROHHAD, and tumours of the sympathetic ganglia. In most people, Exon 3 of the gene contains a sequence of 20 polyalanine repeats. An increase in the number of repeats is associated with congenital central hypoventilation syndrome. There may also be other pathogenic mutations further along the gene.
Organisations involved in researching Phox2B include those concerned with Congenitial Central Hypoventilation Syndrome. These include Keep Me Breathing [11] based in the UK and The CCHS Network based in the USA. The CCHS Network held a scientific conference in September 2023, which covered significant research into Phox2B and CCHS with Keep Me Breathing presenting, too. [12]
Hirschsprung's disease is a birth defect in which nerves are missing from parts of the intestine. The most prominent symptom is constipation. Other symptoms may include vomiting, abdominal pain, diarrhea and slow growth. Most children develop signs and symptoms shortly after birth. However, others may be diagnosed later in infancy or early childhood. About half of all children with Hirschsprung's disease are diagnosed in the first year of life. Complications may include enterocolitis, megacolon, bowel obstruction and intestinal perforation.
Central hypoventilation syndrome (CHS) is a sleep-related breathing disorder that causes ineffective breathing, apnea, or respiratory arrest during sleep. CHS can either be congenital (CCHS) or acquired (ACHS) later in life. The condition can be fatal if untreated. CCHS was once known as Ondine's curse.
Neuroblastoma (NB) is a type of cancer that forms in certain types of nerve tissue. It most frequently starts from one of the adrenal glands but can also develop in the head, neck, chest, abdomen, or spine. Symptoms may include bone pain, a lump in the abdomen, neck, or chest, or a painless bluish lump under the skin.
L1, also known as L1CAM, is a transmembrane protein member of the L1 protein family, encoded by the L1CAM gene. This protein, of 200 to 220 kDa, is a neuronal cell adhesion molecule with a strong implication in cell migration, adhesion, neurite outgrowth, myelination and neuronal differentiation. It also plays a key role in treatment-resistant cancers due to its function. It was first identified in 1984 by M. Schachner who found the protein in post-mitotic mice neurons.
The PAX3 gene encodes a member of the paired box or PAX family of transcription factors. The PAX family consists of nine human (PAX1-PAX9) and nine mouse (Pax1-Pax9) members arranged into four subfamilies. Human PAX3 and mouse Pax3 are present in a subfamily along with the highly homologous human PAX7 and mouse Pax7 genes. The human PAX3 gene is located in the 2q36.1 chromosomal region, and contains 10 exons within a 100 kb region.
Transcription factor 4 (TCF-4) also known as immunoglobulin transcription factor 2 (ITF-2) is a protein that in humans is encoded by the TCF4 gene located on chromosome 18q21.2.
LIM homeobox transcription factor 1-beta, also known as LMX1B, is a protein which in humans is encoded by the LMX1B gene.
Zinc finger E-box-binding homeobox 2 is a protein that in humans is encoded by the ZEB2 gene. The ZEB2 protein is a transcription factor that plays a role in the transforming growth factor β (TGFβ) signaling pathways that are essential during early fetal development.
Cell division cycle 73, Paf1/RNA polymerase II complex component, homolog , also known as CDC73 and parafibromin, is a protein which in humans is encoded by the CDC73 gene.
Gap junction alpha-5 protein (GJA5), also known as connexin 40 (Cx40) — is a protein that in humans is encoded by the GJA5 gene.
Serine/threonine kinase 11 (STK11) also known as liver kinase B1 (LKB1) or renal carcinoma antigen NY-REN-19 is a protein kinase that in humans is encoded by the STK11 gene.
GATA3 is a transcription factor that in humans is encoded by the GATA3 gene. Studies in animal models and humans indicate that it controls the expression of a wide range of biologically and clinically important genes.
Endothelin-3 is a protein that in humans is encoded by the EDN3 gene.
Achaete-scute homolog 1 is a protein that in humans is encoded by the ASCL1 gene. Because it was discovered subsequent to studies on its homolog in Drosophila, the Achaete-scute complex, it was originally named MASH-1 for mammalian achaete scute homolog-1.
Centrosomal protein of 290 kDa is a protein that in humans is encoded by the CEP290 gene. CEP290 is located on the Q arm of chromosome 12.
T-cell leukemia homeobox protein 3 is a protein that in humans is encoded by the TLX3 gene.
Rapid-onset obesity with hypothalamic dysregulation, hypoventilation, and autonomic dysregulation (ROHHAD) is a rare condition whose etiology is currently unknown. ROHHAD mainly affects the endocrine system and autonomic nervous system, but patients can exhibit a variety of signs. Patients present with both alveolar hypoventilation along with hypothalamic dysfunction, which distinguishes ROHHAD from congenital central hypoventilation syndrome (CCHS). ROHHAD is a rare disease, with only 100 reported cases worldwide thus far.
Glucose-6-phosphatase 3, also known as glucose-6-phosphatase beta, is an enzyme that in humans is encoded by the G6PC3 gene.
Hereditary leiomyomatosis and renal cell carcinoma (HLRCC) or Reed's syndrome is rare autosomal dominant disorder associated with benign smooth muscle tumors and an increased risk of renal cell carcinoma. It is characterised by multiple cutaneous leiomyomas and, in women, uterine leiomyomas. It predisposes individuals to renal cell cancer, an association denominated hereditary leiomyomatosis and renal cell cancer. It is also associated with increased risk of uterine leiomyosarcoma. The syndrome is caused by a mutation in the fumarate hydratase gene, which leads to an accumulation of fumarate. The inheritance pattern is autosomal dominant and screening can typically begin in childhood.
Stanislas Lyonnet is a French geneticist. As of 2012 he was Professor of genetics at Paris Descartes University, and a clinical geneticist in the Department of Medical Genetics at the Hôpital Necker - Enfants Malades. His research is aimed at isolating the genes that cause congenital malformation and birth defects.
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