Alternative titles; symbols
Other entities represented in this entry:
HGNC Approved Gene Symbol: PAX7
Cytogenetic location: 1p36.13 Genomic coordinates (GRCh38): 1:18,630,846-18,748,866 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 1p36.13 | Congenital myopathy 19 | 618578 | Autosomal recessive | 3 |
| Rhabdomyosarcoma 2, alveolar | 268220 | Somatic mutation | 3 |
Members of the paired box gene family, including PAX7, encode transcription factors that play important roles in organogenesis and tissue development by regulating the lineage determination and maintenance of progenitor cells (summary by Feichtinger et al., 2019).
Genes (defined as transcription units) that regulate complex integrated functions, such as the programming of early development, often encode proteins with multiple conserved domains. These genes appear to be integrated into functional networks which evolved by duplication and recombination of a small number of primordial genes corresponding to the conserved protein domains. If this is true, it should be possible to start with a single, isolated gene that is part of the network in a particular organism and determine all members of the network. In the second place, the same set of conserved domains is expected to define analogous networks in all organisms linked by evolution. This was the reasoning behind the work of Burri et al. (1989), who isolated human genes HUP1 and HUP2 (PAX3; 606597), which have paired domains very similar to those found in Drosophila genes 'paired' (prd) and 'gooseberry' (gsb), and HUP48 (167411), which has a paired domain similar to that in the Drosophila gene P28 and almost identical to the Pax1 gene of the mouse. The HUP1 and HUP2 genes share the highly conserved octapeptide HSIAGILG found in the prd and gsb genes of Drosophila. The helix-turn-helix structure of their carboxy-terminal portion suggests that these proteins are capable of DNA binding. The HUP2 gene is the site of mutation in the Waardenburg syndrome (193500). HuP1 is the equivalent of Pax7 in the mouse (Gruss and Walther, 1992).
Vorobyov et al. (1997) cloned human PAX7, which encodes a predicted protein of 520 amino acids. Genomic sequence analysis and RT-PCR revealed an alternatively spliced form of PAX7.
By Northern blot analysis of human tissues, Syagailo et al. (2002) detected an approximately 6.3-kb PAX7 transcript exclusively in adult skeletal muscle. RT-PCR of adult human brain showed PAX7 expression in cerebellum and subthalamic nucleus, with weaker expression in temporar and frontal cortex, thalamus, amygdala, and putamen.
Using 3-prime RACE analysis, Vorobyov and Horst (2004) found that both mouse and human PAX7 can be differentially terminated in either exon 8 or exon 9. The resulting splice variants contain or exclude the sequence encoding an evolutionary conserved short C-terminal domain.
Basch et al. (2006) noted that neural crest induction is underway during gastrulation and well before proper neural plate appearance. Basch et al. (2006) showed that a restricted region of chick epiblast (stage 3-4) is specified to generate neural crest cells when explanted under noninducing conditions. This region expresses the transcription factor Pax7 by stage 4+ and later contributes to neural folds and migrating neural crest. In chicken embryos, Pax7 is required for neural crest formation in vivo, because blocking its translation inhibits expression of the neural crest markers Slug (SNAI2; 602150), Sox9 (608160), Sox10 (602229), and HNK1 (see 151290). Basch et al. (2006) concluded that neural crest specification initiates earlier than had been assumed, independently of mesodermal and neural tissues, and that Pax7 has a crucial function during neural crest development.
By yeast 2-hybrid screening and coimmunoprecipitation analysis of mouse C2C12 myoblast cultures and mouse skeletal muscle lysates, Diao et al. (2012) found that mouse Paxbp1 (617621) interacted with Pax3 and Pax7. Paxbp1 coimmunoprecipitated with histone H3 (see 602810) methyltransferase (HMT) activity from C2C12 myoblasts and from mammalian nonmuscle cell lines, and the HMT activity predominantly catalyzed H3 dimethylation and trimethylation. Knockdown of Paxbp1 significantly reduced Pax3- and Pax7-associated HMT activity, and Pax7 or Paxbp1 knockdown reduced proliferation of muscle precursor cells in vitro and mass of tibialis anterior muscle in young mice in vivo. Neither Pax7 nor Paxbp1 were required for proliferation of muscle precursor cells in adult muscle. Paxbp1 interacted directly with the Wdr5 (609012) subunit of the HMT complex. Chromatin immunoprecipitation and reporter gene assays showed that Paxbp1 was recruited to regulatory sites within the Pax7 targets Id3 (600277) and Cdc20 (603618) in C2C12 myoblasts and muscle precursors in vitro. Diao et al. (2012) concluded that Paxbp1 functions as an adaptor that links Wdr5 with Pax7 to recruit HMT to target sites during perinatal muscle cell development in mice.
Pioneer transcription factors establish new cell-fate competence by triggering chromatin remodeling. To identify factors responsible for establishing cell-specific differentially accessible regions (DARs) in chromatin, Mayran et al. (2018) searched for enriched DNA motifs in each DAR repertoire. They found that the mouse melanotrope repertoire was enriched in Pax7 motifs. Experimental approaches showed that Pax7 bound the melanotrope DARs and was required for expression of melanotrope-specific genes. Assessment of chromatin status at Pax7-binding sites in AtT-20 cells before and after Pax7 expression revealed that Pax7 pioneered chromatin opening at a subset of sites that had no previous recognizable chromatin mark and deployed the melanotrope enhancer repertoire. Examination of Pax7-binding sites showed that pioneering appeared in heterochromatin. Pax7 binding took place quickly, but Pax7 required longer than 1 cell division to implement its effect on chromatin organization. Pax7 initiated chromatin remodeling at CpG-methylated enhancers, resulting in loss of DNA methylation and gain of long-term chromatin accessibility, thereby providing long-term chromatin access for nonpioneer transcription factors.
By comparing the RNA-sequencing data from magnetic resonance imaging-guided muscle biopsies, Banerji and Zammit (2019) found that PAX7 target gene repression was an equivalent biomarker to DUX4 (606009) target gene expression for facioscapulohumeral muscular dystrophy (FSHD). PAX7 target gene repression also correlated with histopathologic measures of disease activity independently of DUX4 target gene expression. PAX7 target genes were significantly repressed in single cells from FSHD patients and were able to discriminate DUX4 target gene-negative FSHD myocytes from controls. The authors concluded that PAX7 target gene repression is a superior and more reliable discriminator of FSHD cells than DUX4 target gene expression. They also outlined a pipeline for evaluating PAX7 target gene repression biomarkers and DUX4 target gene expression biomarkers.
By genomic sequence analysis, Vorobyov et al. (1997) determined that the PAX7 gene contains 8 exons.
Vorobyov and Horst (2004) determined that the PAX7 gene contains 9 exons.
By PCR analysis of somatic cell hybrids, Pilz et al. (1993) demonstrated that the PAX7 gene is located on chromosome 1 in the human; it is located on chromosome 4 in the mouse. The human gene is almost certainly on 1p. By analysis of somatic cell hybrids and by fluorescence in situ hybridization (FISH), Stapleton et al. (1993) mapped PAX7 to 1p36.2-p36.12. Schafer and Mattei (1993) mapped PAX7 to 1p36.2-p35 by study of somatic cell hybrids and isotopic in situ hybridization. Shapiro et al. (1993) mapped the PAX7 gene to 1p36 by FISH.
In a review of 28 published cases of the pediatric soft tissue cancer alveolar rhabdomyosarcoma (268220), Whang-Peng et al. (1992) found a characteristic t(2;13)(q35;q14) translocation and a variant t(1;13)(p36;q14) translocation in 64% and 18% of the cases, respectively. Subsequent molecular biology studies demonstrated that these translocations fuse the PAX3 gene (193500) on chromosome 2 or the PAX7 gene on chromosome 1 with the forkhead in rhabdomyosarcoma gene (136533) on chromosome 13 to generate PAX3/FKHR or PAX7/FKHR fusion genes. These genes encode chimeric transcription factors which, in the case of PAX3/FKHR, was shown to activate excessively transcription from binding targets of the wildtype PAX3 transcription factor. Using FISH, RT-PCR, and quantitative Southern blot analyses, Barr et al. (1996) demonstrated that these fusion genes are amplified in 20% of fusion-positive tumors. In particular, they found in vivo amplification of these fusions in 1 of 22 PAX3/FKHR-positive cases and 5 of 7 PAX7/FKHR-positive cases.
Congenital Myopathy-19
In 5 patients from 4 unrelated consanguineous families with congenital myopathy-19 (CMYP19; 618578), Feichtinger et al. (2019) identified homozygous mutations in the PAX7 gene (167410.0001-167410.0004). The mutations, which were found by exome sequencing and confirmed by Sanger sequencing through different research centers, segregated with the disorder in all families. There were 2 nonsense mutations, a splice site mutation, and a missense mutation. Detailed RT-PCR and immunostaining studies on skeletal muscle biopsies from 2 patients showed severely reduced or complete absence of PAX7 and MYF5 (159990) expression, as well as other findings suggesting loss of myogenic satellite cells. The authors suggested a myopathic process that specifically affects muscle stem cells, causing exhaustion of the satellite cell pool that ultimately results in reduced skeletal muscle growth and regeneration.
Associations Pending Confirmation
Proskorovski-Ohayon et al. (2017) reported 2 brothers born to first-cousin parents of Bedouin ancestry with a similar neuromuscular syndrome. Both had severe global developmental delay with no speech or comprehension, pronounced irritability, sleep disorder, aggressive self-mutilation, failure to thrive, microcephaly, and severe axial hypotonia. One had many febrile seizures and 2 episodes of nonfebrile seizures. Deep tendon reflexes were brisk. Ophthalmology evaluation and audiometry were normal. One of the brothers had severe short stature and documented growth hormone deficiency. EMG was normal in both brothers. Quadriceps muscle biopsy performed in 1 patient at the age of 2.5 years demonstrated preserved architecture of skeletal muscle with normal variation in fibers and no evidence of replacement of muscle fibers by fibrous or adipose tissue. No internal nuclei were identified. ATPase stain showed preserved fiber type distribution. There was no evidence of accumulation of lipid or glycogen and no mitochondrial aggregates. Immunohistochemical stains for dystrophins (e.g., 300377), merosin (see 156225), adhalin (600119), and spectrin (see 182810) were positive. Alpha-fetal myosin stain demonstrated several positive, likely regenerative, fibers. Both brothers were homozygous for a mutation in the splice acceptor site of intron 8 of the PAX7 gene, c.1403-2A-G (c.1403-2A-G, NM_001173464.1), which was expected to affect only isoform 3 of PAX7, which contains exon 9 and harbors the unique PHT-OAR domain of the gene. The brothers were also homozygous for a missense mutation in KIF21A (608283). As KIF21A is not expressed in skeletal muscle, this mutation was considered not likely to be involved in the phenotype. Minigene and transfection experiments suggested that the PAX7 splice site mutation results in insertion of 22 basepairs of intron 8 just prior to intron 9, and nonsense-mediated mRNA decay of variant 3. The splice site mutation was not found in homozygous state in 200 ethnically matched controls. Analysis of a human cDNA panel of various tissues showed strong expression of PAX7 isoform 3 in skeletal muscle and brain, weaker expression in testis, and no expression in other tissues.
By representational difference analysis, Seale et al. (2000) isolated mouse Pax7 as a gene specifically expressed in cultured satellite cell-derived myoblasts. In situ hybridization revealed that Pax7 is also expressed in satellite cells residing in adult muscle. Cell culture and electron microscopic analysis showed a complete absence of satellite cells in Pax7 -/- skeletal muscle. Surprisingly, fluorescence-activated cell sorting analysis indicated that the proportion of muscle-derived stem cells was unaffected. Stem cells from Pax7 -/- muscle displayed an almost 10-fold increase in their ability to form hematopoietic colonies. These results demonstrated that satellite cells and muscle-derived stem cells represent distinct cell populations. Furthermore, these studies suggested that induction of Pax7 in muscle-derived stem cells induces satellite cell specification by restricting alternate developmental programs.
Relaix et al. (2005) identified a new cell population that expresses the transcription factors Pax3 (606597) and Pax7 but no skeletal muscle-specific markers. These cells are maintained as a proliferating population in embryonic and fetal muscles of the trunk and limbs throughout development. Using a stable green fluorescent protein (GFP) reporter targeted to Pax3, Relaix et al. (2005) demonstrated that they constitute resident muscle progenitor cells that subsequently become myogenic and form skeletal muscle. Late in fetal development, these cells adopt a satellite cell position characteristic of progenitor cells in postnatal muscle. In the absence of both Pax3 and Pax7, further muscle development is arrested and only the early embryonic muscle of the myotome forms. Cells failing to express Pax3 or Pax7 die or assume a nonmyogenic fate. Relaix et al. (2005) concluded that this resident Pax3/Pax7-dependent progenitor cell population constitutes a source of myogenic cells of prime importance for skeletal muscle formation.
Lepper et al. (2009) demonstrated through the application of inducible Cre/loxP lineage tracing and conditional gene inactivation to the tibialis anterior muscle regeneration paradigm, that, unexpectedly, when Pax7 is inactivated in adult mice, mutant satellite cells are not compromised in muscle regeneration, they can proliferate and reoccupy the sublaminal satellite niche, and they are able to support further regenerative processes. Dual adult inactivation of Pax3 and Pax7 also results in normal muscle regeneration. Multiple time points of gene inactivation revealed that Pax7 is required only up to the juvenile period when progenitor cells make the transition into quiescence. Furthermore, Lepper et al. (2009) demonstrated a cell-intrinsic difference between neonatal progenitor and adult satellite cells in their Pax7 dependency. Lepper et al. (2009) concluded that their finding of an age-dependent change in the genetic requirement for muscle stem cells cautions against inferring adult stem cell biology from embryonic studies, and has direct implications for the use of stem cells from hosts of different ages in transplantation-based therapy.
In a 14-year-old Canadian boy (patient 1), born of consanguineous parents, with congenital myopathy-19 (CMYP19; 618578), Feichtinger et al. (2019) identified a homozygous c.433C-T transition (c.433C-T, NM_002584.2) in exon 3 of the PAX7 gene, resulting in an arg145-to-ter (R145X) substitution. The mutation, which was found by exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. The variant was not found in the ExAC or gnomAD databases. Analysis of patient skeletal muscle cells showed absence of PAX7 mRNA and protein, consistent with a complete loss of function.
In a 5-year-old German girl (patient 2), born of consanguineous parents, with congenital myopathy-19 (CMYP19; 618578) Feichtinger et al. (2019) identified a homozygous G-to-A transition in intron 1 of the PAX7 gene (c.81-1G-A, NM_002584.2), predicted to result in a splice site alteration. The mutation, which was found by exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. The variant was not found in the ExAC or gnomAD databases. Analysis of patient skeletal muscle cells showed severely reduced PAX7 mRNA and protein, consistent with a loss of function.
In a boy (patient 3), born of consanguineous Palestinian parents, who died at age 7 years of congenital myopathy-19 (CMYP19; 618578), Feichtinger et al. (2019) identified a homozygous c.220C-T transition (c.220C-T, NM_002584.2) in exon 2 of the PAX7 gene, resulting in an arg74-to-ter (R74X) substitution. The mutation, which was found by exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. The variant was not found in the ExAC database, but was present at a low frequency in gnomAD (4.06 x 10(-6)). Functional studies of the variant and studies of patient cells were not performed, but the variant was predicted to result in a loss of function.
In 2 sibs (patients 4 and 5), born of consanguineous Saudi Arabian parents, with congenital myopathy-19 (CMYP19; 618578), Feichtinger et al. (2019) identified a homozygous c.166C-T transition (c.166C-T, NM_002584.2) in exon 2 of the PAX7 gene, resulting in an arg56-to-cys (R56C) substitution at a highly conserved residue. The mutation, which was found by exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. The variant was not found in the ExAC or gnomAD databases. Functional studies of the variant and studies of patient cells were not performed.
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