PAX7mutation in a syndrome of failure to thrive, hypotonia, and global neurodevelopmental delay

Abstract

PAX7 encodes a transcription factor essential in neural crest formation, myogenesis, and pituitary lineage specification. Pax7 null mice fail to thrive and exhibit muscle weakness, dying within 3 weeks. We describe a human autosomal-recessive syndrome, with failure to thrive, severe global developmental delay, microcephaly, axial hypotonia, pyramidal signs, dystonic postures, seizures, irritability, and self-mutilation. Aside from low blood carnitine levels, biochemical and metabolic screen was normal, with growth hormone deficiency in one patient. Electromyography was normal, with no specific findings in brain MRI/MRS yet nondemonstrable neuropituitary, a finding of unclear significance. Muscle biopsy showed unaffected overall organization of muscle fibers, yet positive fetal alpha myosin staining, suggesting regeneration. Homozygosity mapping with whole-exome sequencing identified a single disease-associated mutation in PAX7, segregating as expected in the kindred with no homozygosity in 200 ethnically matched controls. Transfection experiments showed that the PAX7 splice-site mutation putatively causes nonsense-mediated mRNA decay affecting onlyPAX7 isoform 3. This isoform, expressed specifically in brain, skeletal muscle and testes, is the sole Pax7 variant normally found in mice. The human muscle phenotype is in line with that in conditional Pax7 null mutant mice, where initial aberrant histological findings resolve postnatally through muscle regeneration.

Paxbp1 controls a key checkpoint for cell growth and survival during early activation of quiescent muscle satellite cells

“…Paxbp1 was originally identified as a Pax7binding protein in the mouse (26). Interestingly, two recent clinical studies reported homozygous mutations in human PAXBP1 and PAX7 that are linked to similar human genetic disorders with global developmental delay and myopathic hypotonia (64,65). Are the defects of Paxbp1-null ASCs linked to Pax7?…”

SEC31A mutation affects ER homeostasis, causing a neurological syndrome

“…Total RNA was isolated from both parents' lymphocytes using GENzol Tri RNA Pure Kit (Geneaid Biotech) according to manufacturer’s instructions. qRT-PCR was performed as previously described 16. Primer sequences will be provided on request.…”

“…Western blot analysis was performed as previously described 16. Protein lysates were extracted from wild-type and SEC31A KO HEK293T cells.…”

Neurogenesis From Neural Crest Cells: Molecular Mechanisms in the Formation of Cranial Nerves and Ganglia

“…The expression of Pax7 is extensive, since it is detected in mesencephalon, rhombencephalon, dorsal NT, fronto-nasal region and NCCs that migrate from the dorsal region of the NT to the pharyngeal arches (Betters et al, 2010;Murdoch et al, 2012). A mutation of Pax7 (isoform 3) was recently found in patients, causing a phenotype of neurodevelopmental delay during development and promoting microcephaly, irritability and self-mutilation among others symptoms (Proskorovski-Ohayon et al, 2017). Therefore, Pax7 is a crucial gene in the induction of NC and in its migration.…”