A novel germline PIGA mutation in Ferro‐Cerebro‐Cutaneous syndrome: A neurodegenerative X‐linked epileptic encephalopathy with systemic iron‐overload

Abstract

Three related males presented with a newly recognized x-linked syndrome associated with neurodegeneration, cutaneous abnormalities, and systemic iron overload. Linkage studies demonstrated that they shared a haplotype on Xp21.3– Xp22.2 and exome sequencing was used to identify candidate variants. Of the segregating variants, only a PIGA mutation segregated with disease in the family. The c.328_330delCCT PIGA variant predicts, p.Leu 110 del (or c.1030_1032delCTT, p. Leu344del depending on the reference sequence). The unaffected great-grandfather shared his X allele with the proband but he did not have the PIGA mutation, indicating that the mutation arose de novo in his daughter. A single family with a germline PIGA mutation has been reported; affected males had a phenotype characterized by multiple congenital anomalies and severe neurologic impairment resulting in infantile lethality. In contrast, affected boys in the family described here were born without anomalies and were neurologically normal prior to onset of seizures after 6 months of age, with two surviving to the second decade. PIGA encodes an enzyme in the GPI anchor biosynthesis pathway. An affected individual in the family studied here was deficient in GPI anchor proteins on granulocytes but not erythrocytes. In conclusion, the PIGA mutation in this family likely causes a reduction in GPI anchor protein cell surface expression in various cell types, resulting in the observed pleiotropic phenotype involving central nervous system, skin, and iron metabolism.

Novel genetic causes for cerebral visual impairment

“…The third glycosylation gene in which a variant was identified, PGAP1 (patient 12, reported elsewhere), is important in the GPI-anchor synthesis pathway. 26 Several other genes, PIGA, PIGN, and PIGT, implicated in this pathway are known to be implicated in CVI and ID as well, 29,[37][38][39][40] and recently, also PGAP1 variants were found to be associated with CVI and ID. 29,41 RERE is another gene with a functional link with a gene known to be aberrant in CVI.…”

Glycosylphosphatidylinositol Anchor Modification Machinery Deficiency Is Responsible for the Formation of Pro-Prion Protein (PrP) in BxPC-3 Protein and Increases Cancer Cell Motility

“…More than 20 genes are known to be important in the synthesis, assembly of the GPI anchor components, cleavage of the GPI-PSS, and eventual en bloc attachment of an assembled GPI anchor to its substrate (21). Mutations in GPI anchor synthesis enzymes are associated with many human diseases; most of these diseases affect neuronal development (22)(23)(24)(25)(26)(27)(28)(29)(30)(31)(32)(33)(34)(35). Furthermore, a lack of GPI anchored protein in cancer cells has also been reported to be due to transcriptional silencing of the genes involved in biosynthesis of the GPI anchor (36).…”

Invited editorial comment—the human phenotype of germline PIGA mutations

“…The family described by Swoboda et al [2013] had a much longer lifespan than did the two other reported families and manifested a number of additional features not seen in those families, most prominently CNS iron deposition and ichthyosiform skin lesions. It does appear that the in-frame deletion that was identified in this family does affect glycosylphosphatidylinositol synthesis, at least in granulocytes, so it is reasonable to conclude that the PIGA mutation is likely responsible for this effect.…”

“…The article by Swoboda et al, [2013] is more intriguing but more challenging to interpret. There are both substantial phenotypic differences and similarities when comparing this family to those described in by Haraklova et al [2013] and Johnston et al [2012].…”