9 research outputs found
Biallelic PRMT7 pathogenic variants are associated with a recognizable syndromic neurodevelopmental disorder with short stature, obesity, and craniofacial and digital abnormalities.
PURPOSE: Protein arginine methyltransferase 7 (PRMT7) is a member of a family of enzymes that catalyzes the methylation of arginine residues on several protein substrates. Biallelic pathogenic PRMT7 variants have previously been associated with a syndromic neurodevelopmental disorder characterized by short stature, brachydactyly, intellectual developmental disability, and seizures. To our knowledge, no comprehensive study describes the detailed clinical characteristics of this syndrome. Thus, we aim to delineate the phenotypic spectrum of PRMT7-related disorder. METHODS: We assembled a cohort of 51 affected individuals from 39 different families, gathering clinical information from 36 newly described affected individuals and reviewing data of 15 individuals from the literature. RESULTS: The main clinical characteristics of the PRMT7-related syndrome are short stature, mild to severe developmental delay/intellectual disability, hypotonia, brachydactyly, and distinct facial morphology, including bifrontal narrowing, prominent supraorbital ridges, sparse eyebrows, short nose with full/broad nasal tip, thin upper lip, full and everted lower lip, and a prominent or squared-off jaw. Additional variable findings include seizures, obesity, nonspecific magnetic resonance imaging abnormalities, eye abnormalities (i.e., strabismus or nystagmus), and hearing loss. CONCLUSION: This study further delineates and expands the molecular, phenotypic spectrum and natural history of PRMT7-related syndrome characterized by a neurodevelopmental disorder with skeletal, growth, and endocrine abnormalities
A homozygous variant disrupting the PIGH startâcodon is associated with developmental delay, epilepsy, and microcephaly
Defective glycosylphosphatidylinositol (GPI)âanchor biogenesis can cause a spectrum of predominantly neurological problems. For eight genes critical to this biological process, disease associations are not yet reported. Scanning exomes from 7,833 parentâchild trios and 1,792 singletons from the DDD study for biallelic variants in this geneâset uncovered a rare PIGH variant in a boy with epilepsy, microcephaly, and behavioral difficulties. Although only 2/2 reads harbored this c.1A > T transversion, the presence of âŒ25 Mb autozygosity at this locus implied homozygosity, which was confirmed using Sanger sequencing. A similarlyâaffected sister was also homozygous. FACS analysis of PIGHâdeficient CHO cells indicated that cDNAs with c.1A > T could not efficiently restore expression of GPIâAPs. Truncation of PIGH protein was consistent with the utilization of an inâframe startâsite at codon 63. In summary, we describe siblings harboring a homozygous c.1A > T variant resulting in defective GPIâanchor biogenesis and highlight the importance of exploring lowâcoverage variants within autozygous regions
A homozygous variant disrupting the PIGH startâcodon is associated with developmental delay, epilepsy, and microcephaly
Defective glycosylphosphatidylinositol (GPI)âanchor biogenesis can cause a spectrum of predominantly neurological problems. For eight genes critical to this biological process, disease associations are not yet reported. Scanning exomes from 7,833 parentâchild trios and 1,792 singletons from the DDD study for biallelic variants in this geneâset uncovered a rare PIGH variant in a boy with epilepsy, microcephaly, and behavioral difficulties. Although only 2/2 reads harbored this c.1A > T transversion, the presence of âŒ25 Mb autozygosity at this locus implied homozygosity, which was confirmed using Sanger sequencing. A similarlyâaffected sister was also homozygous. FACS analysis of PIGHâdeficient CHO cells indicated that cDNAs with c.1A > T could not efficiently restore expression of GPIâAPs. Truncation of PIGH protein was consistent with the utilization of an inâframe startâsite at codon 63. In summary, we describe siblings harboring a homozygous c.1A > T variant resulting in defective GPIâanchor biogenesis and highlight the importance of exploring lowâcoverage variants within autozygous regions
Role of nitric oxide in tumor angiogenesis
Nitric oxide (NO) is an important signalling molecule that acts in many tissues to regulate different physiological and pathological processes. We have contributed to demonstrate that NO stimulates angiogenesis and mediates the effect of different angiogenic molecules. In human tumors NOS expression and activity correlate with tumor growth and aggressiveness, through angiogenesis stimulation and regulation of angiogenic factor expression. Drugs affecting the NOS pathway appear promising antitumor strategies by reducing edema, inhibiting angiogenesis and facilitating the delivery of chemotherapeutical agents