Congenital disorder of glycosylphosphatidylinositol (GPI)-anchor biosynthesis—The phenotype of two patients with novel mutations in the PIGN and PGAP2 genes

Jezela‐Stanek, Aleksandra; Ciara, Elżbieta; Piekutowska‐Abramczuk, Dorota; Trubicka, Joanna; Jurkiewicz, Elżbieta; Rokicki, Dariusz; Mierzewska, Hanna; Spychalska, Justyna; Uhrynowska, Małgorzata; Szwarc-Bronikowska, Marta; Buda, Piotr; Said, Abdul Rahim; Jamroz, Ewa; Rydzanicz, Małgorzata; Płoski, Rafał; Krajewska‐Walasek, M; Pronicka, Ewa

doi:10.1016/j.ejpn.2016.01.007

Cited by 44 publications

(57 citation statements)

References 33 publications

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“…47 Using PIGN- knockout HEK293 cells, we confirmed that p.(L311W) results in reduced PIGN activity. Jezela-Stanek et al 25 recently described a similar case with a relatively mild phenotype (seizures, developmental delay and hypotonia) and reduced expression of GPI-APs in patient granulocytes. It is interesting to note that the p.(L311W) variant is also shared in common between these two milder cases.…”

Section: Discussionmentioning

confidence: 93%

“…Both variants have been described recently; a homozygous p.(K232*) mutation was seen in a fetus diagnosed with Fryns syndrome, 24 a condition characterised by multiple congenital anomalies, while p.(L311W) was observed in an individual where the phenotype was limited to hypotonia, developmental delay and seizures. 25 …”

Section: Resultsmentioning

confidence: 99%

“…In two cases, we upgraded an inferred classification of ‘likely pathogenic' to ‘pathogenic'. For instance, although the p.(L311W) variant in PIGN has been described before, 25 this was only in a single affected individual and so we could not invoke PS4, which requires multiple prior observations. But together with the modest co-segregation seen in our family (again, not reaching the level to invoke PP1) and the robust functional experiments performed here using mutant HEK293 cells (Figure 2) and by Jezela-Stanek using patient cells, this was enough to persuade us that this variant is pathogenic.…”

Section: Discussionmentioning

confidence: 99%

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Analysis of exome data for 4293 trios suggests GPI-anchor biogenesis defects are a rare cause of developmental disorders

et al. 2017

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Over 150 different proteins attach to the plasma membrane using glycosylphosphatidylinositol (GPI) anchors. Mutations in 18 genes that encode components of GPI-anchor biogenesis result in a phenotypic spectrum that includes learning disability, epilepsy, microcephaly, congenital malformations and mild dysmorphic features. To determine the incidence of GPI-anchor defects, we analysed the exome data from 4293 parent–child trios recruited to the Deciphering Developmental Disorders (DDD) study. All probands recruited had a neurodevelopmental disorder. We searched for variants in 31 genes linked to GPI-anchor biogenesis and detected rare biallelic variants in PGAP3, PIGN, PIGT (n=2), PIGO and PIGL, providing a likely diagnosis for six families. In five families, the variants were in a compound heterozygous configuration while in a consanguineous Afghani kindred, a homozygous c.709G>C; p.(E237Q) variant in PIGT was identified within 10–12 Mb of autozygosity. Validation and segregation analysis was performed using Sanger sequencing. Across the six families, five siblings were available for testing and in all cases variants co-segregated consistent with them being causative. In four families, abnormal alkaline phosphatase results were observed in the direction expected. FACS analysis of knockout HEK293 cells that had been transfected with wild-type or mutant cDNA constructs demonstrated that the variants in PIGN, PIGT and PIGO all led to reduced activity. Splicing assays, performed using leucocyte RNA, showed that a c.336-2A>G variant in PIGL resulted in exon skipping and p.D113fs*2. Our results strengthen recently reported disease associations, suggest that defective GPI-anchor biogenesis may explain ~0.15% of individuals with developmental disorders and highlight the benefits of data sharing.

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Section: Discussionmentioning

confidence: 93%

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Analysis of exome data for 4293 trios suggests GPI-anchor biogenesis defects are a rare cause of developmental disorders

et al. 2017

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“…For the 12 patients reported in this cohort, intellectual disability, severe motor developmental delay and seizures were the most predominant features. Only a minority of patients manifested additional features …”

Section: Resultsmentioning

confidence: 99%

Clinical variability in inherited glycosylphosphatidylinositol deficiency disorders

et al. 2018

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It is estimated that 0.5% of all mammalian proteins have a glycosylphosphatidylinositol (GPI)-anchor. GPI-anchored proteins (GPI-APs) play key roles, particularly in embryogenesis, neurogenesis, immune response and signal transduction. Due to their involvement in many pathways and developmental events, defects in the genes involved in their synthesis and processing can result in a variety of genetic disorders for which affected individuals display a wide spectrum of features. We compiled the clinical characteristics of 202 individuals with mutations in the GPI biosynthesis and processing pathway through a review of the literature. This review has allowed us to compare the characteristics and the severity of the phenotypes associated with different genes as well as highlight features that are prominent for each. Certain combinations, such as seizures with aplastic/hypoplastic nails or abnormal alkaline phosphatase levels suggest an inherited GPI deficiency, and our review of all clinical findings may orient the management of inherited GPI deficiencies.

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“…Mutations in more than 13 PIG and PGAP genes have been described to cause inherited GPI deficiencies. All are autosomal recessive except PIGA which is inherited as X‐linked recessive trait with very wide phenotypic spectrum …”

Section: Introductionmentioning

confidence: 99%

PGAP3‐related hyperphosphatasia with mental retardation syndrome: Report of 10 new patients and a homozygous founder mutation

et al. 2017

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Background Hyperphosphatasia with mental retardation syndrome (HPMRS) is caused by recessive mutations in genes involved in the glycosylphosphatidylinsitol pathway, including PGAP3. Materials and Methods We describe 10 patients from 8 Egyptian families presenting with developmental delay, severe intellectual disability, distinct facial dysmorphism and increased alkaline phosphatase. Sanger sequencing of PGAP3 was performed. Results Eight patients had cleft palate, 4 had postnatal microcephaly and 5 had seizures. Neuro‐imaging findings showed thin corpus callosum in 9 patients, mild ventriculomegaly in 3 patients and variable degrees of cerebellar vermis hypoplasia in 4 patients, a finding not previously reported in patients with HPMRS. Additional manifestations included double row teeth, hypogenitalism and congenital heart disease. Biallelic loss of function mutations in the PGAP3 gene were detected in all patients. Nine patients were homozygous for the c.402dupC (p.M135Hfs*28) mutation strongly suggesting a founder effect. On the other hand, 1 patient had a novel mutation, c.817_820delGACT (p.D273Sfs*37). Conclusion This is the largest series of patients with HPMRS from same ethnic group. Our results reinforce the distinct clinical and facial features of PGAP3‐related HPMRS which are the clue for targeted genetic testing. Moreover, we present additional unreported clinical and neuro‐imaging findings and a novel mutation thus expanding the phenotypic and mutational spectrum of this rare disorder.

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Congenital disorder of glycosylphosphatidylinositol (GPI)-anchor biosynthesis—The phenotype of two patients with novel mutations in the PIGN and PGAP2 genes

Cited by 44 publications

References 33 publications

Analysis of exome data for 4293 trios suggests GPI-anchor biogenesis defects are a rare cause of developmental disorders

Analysis of exome data for 4293 trios suggests GPI-anchor biogenesis defects are a rare cause of developmental disorders

Clinical variability in inherited glycosylphosphatidylinositol deficiency disorders

PGAP3‐related hyperphosphatasia with mental retardation syndrome: Report of 10 new patients and a homozygous founder mutation

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