Alternative titles; symbols
HGNC Approved Gene Symbol: PHOX2B
SNOMEDCT: 719972004;
Cytogenetic location: 4p13 Genomic coordinates (GRCh38) : 4:41,744,082-41,748,725 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 4p13 | {Neuroblastoma, susceptibility to, 2} | 613013 | 3 | |
| Central hypoventilation syndrome, congenital, 1, with or without Hirschsprung disease | 209880 | Autosomal dominant | 3 | |
| Neuroblastoma with Hirschsprung disease | 613013 | 3 |
Yokoyama et al. (1996) identified the PHOX2B gene, which they called NBPhox for 'neuroblastoma phox,' from a 3-prime-directed cDNA library derived from the human neuroblastoma cell line CHP134. PHOX2B has an mRNA of 3,074 nucleotides and contains an open reading frame of 314 amino acids spanning nucleotides 361 to 1,302. The polyadenylation signal AATAAA is located 17 bases upstream from the site of polyadenylation. The gene encodes a protein with a homeodomain that is significantly homologous with those in various members of the paired-type homeobox genes. The amino acid sequences of the homeodomains of PHOX2B and PHOX2A (602753) cover 60 amino acids and are identical, but outside the homeodomain no significant sequence similarity was observed. A proline-rich domain lies between amino acids 192 and 284 of the PHOX2B protein, and a glycine-rich domain lies between amino acids 196 and 289. There are 2 alanine-rich repeats in the C terminus of the homeodomain.
Pattyn et al. (1997) cloned the mouse Phox2b gene. The homeodomains of mouse Phox2a and Phox2b are identical. The N-terminal domains of mouse Phox2a and Phox2b are 57% identical, but the C-terminal domains are highly divergent. The murine Phox2b gene also contains 2 alanine stretches in the C terminus.
Pattyn et al. (1997) studied the expression pattern of Phox2b. In embryonic day 9 brains, 2 ventral columns of Phox2b-positive cells ran on either side of the floor plate from an abrupt rostral limit just anterior to the rhombomere1/rhombomere2 boundary into the cervical spinal cord. One day later the ventral column was still strongly labeled. Two ventral patches on both sides of the met-mesencephalic border could be identified at later stages as, respectively, the forming trochlear and oculomotor nuclei. By embryonic day 11.5, the ventral columns had disappeared, whereas the dorsal column contained many more Phox2b-positive cells. In the neonatal brain, Phox2b expression was similar to that of Phox2a. No expression was seen in the spinal cord. In the peripheral nervous system, Phox2b, like Phox2a, was expressed in 3 cranial sensory ganglia and in all ganglia of the autonomic nervous system as early as they had formed, and at least up to midgestation. Although the list of Phox2b expression sites was strikingly similar to that reported for Phox2a, Pattyn et al. (1997) observed systematic differences in onset, persistence, and extent of expression. The expression pattern of Phox2b in Phox2a-null mice indicated that Phox2a regulates Phox2b directly or indirectly in cranial ganglia.
Amiel et al. (2003) showed that PHOX2B is expressed in both the central and the peripheral autonomic nervous system during human embryonic development.
Espinosa-Medina et al. (2014) studied how parasympathetic ganglia form close to visceral organs as well as what their precursors are and found that many cranial nerve-associated crest cells coexpress the panautonomic determinant PHOX2B together with markers of Schwann cell precursors. Some give rise to Schwann cells after downregulation of PHOX2B. Others form parasympathetic ganglia after being guided to the site of ganglion formation by the nerves that carry preganglionic fibers, a parsimonious way of wiring the pathway. Espinosa-Medina et al. (2014) concluded that cranial Schwann cell precursors are the source of parasympathetic neurons during normal development.
Amiel et al. (2003) stated that the PHOX2B gene maps to chromosome 4p12.
Congenital Central Hypoventilation Syndrome 1
Because in mice the development of reflex circuits of the autonomic nervous system is dependent on the Phox2b gene, Amiel et al. (2003) investigated its human ortholog, PHOX2B, in 29 individuals with congenital central hypoventilation syndrome (CCHS1; 209880). This syndrome is a life-threatening disorder involving an impaired ventilatory response to hypercarbia and hypoxemia. The core phenotype is associated with lower-penetrance anomalies of the autonomic nervous system including Hirschsprung disease and tumors of neural crest derivatives such as ganglioneuromas and neuroblastomas. Amiel et al. (2003) found that 18 of the 29 patients had heterozygous de novo mutations in PHOX2B. Most mutations consisted of 5-9 alanine expansions within a 20-residue polyalanine tract (603851.0001) probably resulting from nonhomologous recombination. In 2 CCHS cases, a de novo cytosine insertion in a stretch of 4 cytosines (603851.0002) and a deletion of 37 nucleotides (603851.0003) resulted in a frameshift downstream of the homeobox, predicting a mutant protein with no known function or homology. Amiel et al. (2003) found 2 individuals who in addition to polyalanine expansions in PHOX2B had heterozygous variants in genes involved in the same developmental pathway; these variants were amino acid substitutions pro1039 to leu in RET (164761.0046) and arg93 to trp in GDNF (600837.0001), respectively. Phox2 genes control Ret expression in both sympathetic and enteric neurons in mice. Unlike the polyalanine expansions, however, these variants are neither necessary (most individuals with CCHS do not have any RET or GDNF gene variant) nor sufficient for the disease to occur (carrier parents have no phenotypic expression). Amiel et al. (2003) concluded that PHOX2B is a primary disease locus in CCHS. They found mutations in PHOX2B not only in isolated cases of CCHS but also in individuals with a more complex neural crest involvement including CCHS and Hirschsprung disease (Haddad syndrome) as well as early-onset neuroblastoma. They found no correlation between the size of the polyalanine tract and the complexity of the disease.
Sasaki et al. (2003) studied 7 patients with isolated CCHS and 3 CCHS patients with Hirschsprung disease. In 4 patients they detected polyalanine expansions in the PHOX2B gene and in 1 patient a novel frameshift mutation in PHOX2B. They could not reject the possibility that mutations in the RET (164761), GDNF, PHOX2A, and HASH1 (100790) genes may also be involved in the pathogenesis of CCHS.
In 65 of 67 CCHS probands (97%), Weese-Mayer et al. (2003) found heterozygosity for the exon 3 polyalanine expansion mutation in PHOX2B. There was an association between repeat mutation length and severity of the CCHS/ANSD (autonomic nervous system dysregulation and/or dysfunction) phenotype. Of the 2 probands who did not carry the expansion mutation, one had a nonsense mutation in exon 3 that truncated the protein and the other had no mutation in PHOX2B but had a previously reported EDN3 frameshift point mutation.
Matera et al. (2004) screened the PHOX2B gene in 27 patients with CCHS, including 3 with associated Hirschsprung disease and 3 with late-onset CCHS, and identified 3 heterozygous frameshift mutations and 22 polyalanine expansions ranging from 5 to 13 residues. The authors noted that phenotype severity increased with increasing polyalanine expansion size. Polyalanine triplet expansions were also detected in the affected sibs of 2 familial cases and in 2 asymptomatic parents.
Trochet et al. (2005) reported the clinical and molecular assessments of a cohort of 188 probands with CCHS, either isolated or associated with Hirschsprung disease (the association known as Haddad syndrome) and/or tumors of the sympathetic nervous system (TSNS). A heterozygous mutation of the PHOX2B gene was identified in 174 of the 188 cases (92.6%). In 161 (92.5%) of the 174 cases with an identifiable mutation, the mutation consisted of an in-frame duplication of 15 to 39 nucleotides, leading to an expansion of +5 to +13 alanines within the 20-alanine tract of the carboxy terminal of the homeodomain of the protein. Vertical transmission of an alanine expansion (+5 and +7 alanines) from an affected parent to his or her affected child was demonstrated in 2 cases. In a third familial case, with recurrence in sibs, Trochet et al. (2005) detected paternal somatic mosaicism for the mutation that was identified in the index case (+7 alanines). Somatic mosaicism was detected in 10 cases (6 fathers and 4 mothers). In all cases, the nucleotide in-frame duplication leading to an alanine expansion remained unchanged in transmission, suggesting that such polyalanine expansions are both meiotically and mitotically stable. These data argued for unequal allelic homologous recombination as the mutation-causing mechanism, as proposed by Warren (1997) for the alanine expansion in the HOXD13 gene (142989) resulting in synpolydactyly (186000). In 5 of 9 patients with late-onset central hypoventilation syndrome, as described by Katz et al. (2000), Trochet et al. (2005) found an expansion of +5 alanines in the PHOX2B gene (603851.0001). From genotype-phenotype correlations, Trochet et al. (2005) came to the conclusion that patients with CCHS who develop malignant tumors of the sympathetic nervous system harbor either a missense (e.g., 603851.0005) or frameshift heterozygous mutation of the PHOX2B gene.
Bachetti et al. (2005) tested the transcriptional activity of wildtype and mutant PHOX2B expression constructs on the regulatory regions of 2 target genes, DBH (609312) and PHOX2A (ARIX; 602753). Two sets of mutations played different roles in transcriptional regulation of these genes, showing a correlation between length of polyalanine expansions and severity of reduced transcriptional activity. In particular, although reduced transactivation due to polyalanine expansions may be caused by retention of the mutated protein in the cytoplasm or in the nuclear aggregates, frameshift mutations did not impair PHOX2B nuclear localization, suggesting a different mechanism through which frameshift mutations exert the observed effects on target promoters. Moreover, a 614delC deletion seemed to cause sequestration of the corresponding mutant PHOX2B in the nucleolar compartment.
Trochet et al. (2005) investigated aggregate formation by proteins with polyalanine tract expansions ranging from +5 to +13 alanines using immunofluorescence of transfected cells and gel filtration of in vitro translated proteins. Transactivation of the dopamine beta-hydroxylase promoter by PHOX2B proteins with frameshift and missense mutations was abolished or severely curtailed, as was in vitro DNA binding, although the proteins localized to the nucleus. The transactivation potential of proteins with polyalanine tract expansions declined with increasing length of the polyalanine stretch, and DNA binding was affected for an expansion of +9 alanines and above. Cytoplasmic aggregation in transfected cells was only observed for the longest expansions, whereas even the short expansion mutants were prone to form multimers in vitro. Trochet et al. (2005) proposed that such a tendency to protein misfolding could explain loss of transactivation for alanine expansion mutations.
Lombardo et al. (2018) reported 6 patients with CCHS who had cardiac anomalies. Only 1 had an expansion of the polyalanine tract (603851.0001), and this patient required tracheostomy with continuous mechanical ventilation and had Hirschsprung disease. One had a whole-gene deletion. Two patients had missense mutations involving the homeobox domain (R141Q, 603851.0009; R149L, 603851.0010). Two had a recurrent premature termination codon (Y78X; 603851.0011).
Sivan et al. (2019) reported a male infant with CCHS who had compound heterozygous mutations in the PHOX2B gene: a polyalanine repeat expansion (24 alanine repeats; 603851.0001) and a missense mutation (G262V; 603851.0012). The polyalanine repeat expansion was seen in the father, paternal grandfather, and 2 out of 5 of the father's sibs, and the missense mutation was seen in the mother, maternal grandfather, and 3 out of 9 of the mother's sibs. All family members, other than the proband, were phenotypically normal. The authors concluded that this was the first reported case of compound heterozygosity for variants in the PHOX2B gene in a proband with CCHS in which neither variant alone was sufficient to cause disease in multiple family members. The authors noted the importance of PHOX2B testing in parents of all probands with CCHS to identify mosaicism in a parent, confirm allele pathogenicity, determine inheritance, and provide information for future pregnancy planning. The authors also suggested sequencing of PHOX2B if a polyalanine repeat expansion has been identified, especially when the phenotype is more severe than expected.
In a male infant with CCHS and Haddad Syndrome, Guzoglu et al. (2020) identified a c.722_759del38 deletion in the PHOX2B gene within a polyalanine tract (see 603851.0003). The mutation was identified by direct gene sequencing.
Susceptibility to Neuroblastoma 2
Trochet et al. (2004) noted that rare familial cases of neuroblastoma (NBLST2; 613013) and its association with other genetically determined congenital malformations of neural crest-derived cells, namely HSCR and/or CCHS, suggested that there may be a gene or genes in which germline mutations predispose to neuroblastoma. Because of the demonstration that PHOX2B is the major disease-causing gene in isolated and syndromic CCHS, Trochet et al. (2004) investigated it as a candidate gene in neuroblastoma. They reported germline mutations of PHOX2B in both a familial case of neuroblastoma (603851.0005) and a patient with neuroblastoma associated with HSCR (603851.0006). PHOX2B was the first gene in which germline mutations were demonstrated to predispose to neuroblastoma.
Associations Pending Confirmation
Toyota et al. (2004) found that a subtype of strabismus, constant exotropia, displayed marked association with schizophrenia (see 181500) (p = 0.00000000906). They identified frequent deletion/insertion polymorphisms in the 20-alanine homopolymer stretch of the PMX2B gene, with a modest association between these functional polymorphisms and constant exotropia in schizophrenia as compared to control samples (p = 0.029). The polymorphisms were also associated with overall schizophrenia (p = 0.012) and more specifically with schizophrenia manifesting strabismus (p = 0.004). These results suggested a possible interaction between PMX2B and other schizophrenia-precipitating factors, increasing the risk of the combined phenotypes.
Benailly et al. (2003) reported a 16-month-old girl with a syndrome encompassing developmental delay, severe hypotonia, facial dysmorphism, and short-segment Hirschsprung disease, who was found to have a de novo t(4;8)(p13;p22) translocation. A comparative genomic hybridization (CGH) study found a 5-Mb deletion at chromosome 4p12-p13 that included the PMX2B gene. Dysmorphic features included frontal bossing, prominent forehead, angioma on the forehead, very short nose with slightly anteverted nostrils, high nasal bridge, prominent philtral borders, bilateral epicanthus, and an open anterior fontanel. She had discrete rhizomelia and the anus was anteriorly placed. The authors suggested that PMX2B haploinsufficiency may predispose to Hirschsprung disease.
Pattyn et al. (1999) generated mice deficient in Phox2b by homologous recombination. In Phox2b -/- mice, autonomic ganglia failed to form properly and degenerate, as did the 3 cranial sensory ganglia that are part of the autonomic reflex circuits. In the anlagen of the enteric nervous system in the sympathetic ganglia, Phox2b is needed for the expression of the GDNF-receptor subunit Ret (164761) and for maintaining Mash1 (100790) expression. Mutant ganglionic anlagen also failed to switch on the genes that encode dopamine-beta-hydroxylase and tyrosine hydroxylase, both needed for the biosynthesis of the neurotransmitter noradrenaline, demonstrating that Phox2b regulates the noradrenergic phenotype in vertebrates.
Dilp1 is a semidominant mouse mutation that causes dilated pupils when heterozygous and is lethal when homozygous. Cross et al. (2004) reported a nonsense Phox2b mutation in Dilp1 mice. Mice carrying a targeted allele of Phox2b also had dilated pupils; the 2 alleles did not complement. The ciliary ganglion was atrophic in Phox2b heterozygous mutants. Some patients with congenital central hypoventilation syndrome (CCHS; 209880) have ocular abnormalities, including constricted rather than dilated pupils. The apparent phenotypic differences between mice carrying a loss-of-function mutation of Phox2b and CCHS patients indicates that PHOX2B mutations found in CCHS patients, all of which can produce proteins with intact DNA-binding domains, are gain-of-function mutations that alter rather than abolish protein function.
Dubreuil et al. (2008) found that mice heterozygous for the CCHS-causing expanded alanine tract in the Phox2b gene (603851.0001) had irregular breathing, did not respond to an increase in CO2, and died soon after birth from central apnea. Postmortem examination showed specific loss of Phox2b-expressing glutamatergic neurons in the retrotrapezoid nucleus/parafacial region, whereas other areas thought to be involved in breathing regulation were anatomically normal. The findings demonstrated the essential role of a specific population of medullary interneurons in driving proper breathing at birth.
In 16 of 29 patients with congenital central hypoventilation syndrome (CCHS1; 209880), some of whom also had Hirschsprung disease and ganglioneuroblastoma or neuroblastoma, Amiel et al. (2003) found a triplet expansion of 15 to 27 nucleotides (nucleotides 721-780) of the PHOX2B gene, adding 5 to 9 alanines to the 20-residue polyalanine tract. Most mutant genotypes were different, suggesting that they derived from independent mutational events. The polyalanine triplet expansion was shown to be de novo in cases where parents were available. Two of these patients also carried mutations in RET (P1039L; 164761.0046) or GDNF (603851.0001).
In 5 of 9 patients with late-onset central hypoventilation syndrome, Trochet et al. (2005) found an expansion of 5 alanines in the PHOX2B polyalanine tract.
Antic et al. (2006) reported 5 adults with late-onset central hypoventilation syndrome who each had a heterozygous expansion of 5 alanines in the PHOX2B polyalanine tract.
Arai et al. (2007) determined that de novo PHOX2B polyalanine expansions in 6 informative CCHS families resulted from unequal crossover or unequal sister chromatid exchange during spermatogenesis. In contrast to polyglutamine expansions, which usually result from strand slippage, Arai et al. (2007) suggested that polyalanine expansions probably result from misalignment due to the secondary DNA structure of imperfect trinucleotide repeats (GCA, GCG, GCC, and GCT) that encode polyalanine tracts.
Sivan et al. (2019) reported a male infant with CCHS who had compound heterozygous mutations in the PHOX2B gene: a polyalanine repeat expansion (24 alanine repeats) and a c.785G-T transversion in exon 3, resulting in a gly262-to-val (G262V) substitution (603851.0012). The polyalanine repeat expansion was seen in the father, paternal grandfather, and 2 out of 5 of the father's sibs, and the missense mutation was seen in the mother, maternal grandfather, and 3 out of 9 of the mother's sibs. All family members, other than the proband, were phenotypically normal. The authors concluded that this was the first reported case of compound heterozygosity for variants in the PHOX2B gene in a proband with CCHS in which neither variant alone was sufficient to cause disease in multiple family members. The authors noted the importance of PHOX2B testing in parents of all probands with CCHS to identify mosaicism in a parent, confirm allele pathogenicity, determine inheritance, and provide information for future pregnancy planning. The authors also suggested sequencing of PHOX2B if a polyalanine repeat expansion has been identified, especially when the phenotype is more severe than expected.
In a patient with congenital central hypoventilation syndrome (CCHS1; 209880), Amiel et al. (2003) found a de novo cytosine insertion in a stretch of 4 cytosines, 618_619insC, in the PHO2B gene.
In a patient with congenital central hypoventilation syndrome (CCHS1; 209880), Amiel et al. (2003) found a deletion of 37 nucleotides (722_759del37) in the PHOX2B gene, resulting in a frameshift downstream of the homeobox. The deletion could be considered an out-of-frame contraction of the polyalanine tract.
In a familial case of neuroblastoma (613013), Trochet et al. (2004) identified a heterozygous 299G-T transversion in exon 2 of the PHOX2B gene, resulting in an arg100-to-leu (R100L) mutation in the homeodomain of the protein. The proband, a male, was the first child born to nonconsanguineous parents. A multifocal abdominal ganglioneuroma was surgically removed at the age of 10 years. His younger brother presented at age 6 years with an abdominal neuroblastoma which was surgically removed, and experienced local recurrences 18 months and 30 months later. No amplification of MYCN (164840) was detected. The father had a ganglioneuroma of the adrenal medulla, which was surgically removed at age 44 years.
In a male patient born to nonconsanguineous parents with a combination of Hirschsprung disease (142623) and neuroblastoma (see 613013), Trochet et al. (2004) identified heterozygosity for a 421C-G transversion in exon 2 of the PHOX2B gene, resulting in an arg141-to-gly (R141G) mutation. HSCR was diagnosed in the neonatal period and was treated surgically, with a good result. Multifocal tumors, both thoracic and abdominal, were found at age 9 months and were surgically removed. No amplification of MYCN (164840) was detected. The R141G mutation in this patient was inherited from the healthy mother. Several hypotheses could explain this observation: the tumor may develop in adulthood, the tumor may spontaneously regress (a well-known phenomenon for neuroblastoma), or there may be incomplete penetrance, which is higher for tumor predisposition than for HSCR and has been suspected in neuroblastoma (Maris et al. (1997, 2002)).
In affected members of a family previously described by Maris et al. (2002) in which 7 members spanning 3 generations had neuroblastoma (613013), 2 of whom also had Hirschsprung disease (142623), Mosse et al. (2004) identified a heterozygous 1-bp deletion in the PHOX2B gene, 676delG, resulting in a frameshift and a slightly truncated protein lacking the second polyalanine tract. The mutation segregated with neuroblastoma through all 3 generations. The family had previously been shown to cosegregate a 16p13-p12 haplotype with neuroblastoma. The proband, who was affected with neuroblastoma, Hirschsprung disease, and neurofibromatosis type I (162200), had previously been shown to have an inactivating mutation in the NF1 gene, 3775delT (613113.0037), which was not present in either parent. Mosse et al. (2004) concluded that the presence of 2 germline mutations in the proband, as well as evidence of linkage to 16p in the family, suggested an oligogenic mechanism for neuroblastoma initiation, as had been shown for other diseases of neural crest-derived tissues (Gabriel et al., 2002).
In 2 affected members of a family with neuroblastoma (613013), McConville et al. (2006) identified a constitutional heterozygous 590G-A transition in the PHOX2B gene, resulting in a gly197-to-asp (G197D) substitution in a conserved residue outside of the homeodomain. No tumor DNA was available. The index case, from whom no DNA was available, died at age 5 years with metastatic neuroblastoma and ganglioneuroblastoma. Her father and paternal grandmother, both of whom had the G197D mutation, had adult-onset ganglioneuroblastoma. Another paternal relative, from whom DNA was not available, died at age 14 years from ganglioneuroblastoma. Two unaffected sibs of the index patient's grandmother also carried the mutation, indicating incomplete penetrance. None of the family members had Hirschsprung disease (142623) or any features of autonomic dysfunction. The mutation was not identified in 284 controls.
In a white female (P005) with congenital central hypoventilation syndrome (CCHS1; 209880) and an adrenal ganglioneuroma, but no evidence of Hirschsprung disease, Lombardo et al. (2018) identified a c.422G-A transition in exon 2 of the PHOX2B gene that resulted in an arginine-to-glutamine substitution at codon 141 (R141Q) in the homeobox domain of the protein. This patient had separate origin of the left vertebral artery off the aortic arch.
Hamosh (2020) noted that the R141Q variant was absent from the gnomAD database on April 12, 2020.
In an African American female (P003) with central hypoventilation syndrome (CCHS1; 209880), Lombardo et al. (2018) identified a c.446G-T transversion in exon 3 of the PHOX2B gene, resulting in an arginine-to-leucine substitution at codon 149 (R149L) in the homeobox domain of the protein. This patient also had moderate secundum atrial septal defect (ASD) and a patent ductus arteriosus (PDA) that required surgical closure at age 5 years.
Hamosh (2020) noted that the A149L variant was absent from the gnomAD database on April 12, 2020.
In 2 unrelated African American females (P008 and P018) with central hypoventilation syndrome (CCHS1; 209880), 1 of whom had Hirschsprung disease, Lombardo et al. (2018) identified a c.234C-G transversion in exon 1 of the PHOX2B gene that resulted in a tyrosine-to-termination substitution at amino acid 78 (Y78X). Both of these patients also had congenital heart disease (CHD).
Hamosh (2020) noted that the Y78X variant was absent from the gnomAD database on April 12, 2020.
For discussion of the c.785G-T transversion in exon 3 of the PHOX2B gene, resulting in a gly262-to-val (G262V) substitution, that was found in compound heterozygous state in a proband with congenital central hypoventilation syndrome (CCHS1; 209880) by Sivan et al. (2019), see 603851.0001.
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