Abstract
Glycosylphosphatidylinositol (GPI) is a glycolipid that anchors 150 or more kinds of proteins to the cell surface. There are at least 26 genes involved in the biosynthesis and transport of GPI anchored proteins (GPI-APs). In paroxysmal nocturnal hemogrobinuria (PNH), an acquired GPI deficiency, somatic mutation in X-linked PIGA accounts for most of the patients. A case with PNH due to a combination of inherited mutation in one allele and a somatic mutation in the other allele of autosomal gene PIGT was reported recently (Blood 2013 doi:10.1182/blood-2013-01-481499). On the other hand, many inherited GPI deficiencies (IGDs) were found recently using whole exome sequencing (Nat Genet 2010 vol.42 p827, Am J Hum Genet 2012 vol. 90 p295, p146, Am J Hum Genet 2012 vol. 91 p146, Am J Hum Genet 2013 vol. 92 p584). As the complete GPI deficiency causes embryonic death, these patients with IGD are partial deficiency. The major symptoms of IGDs include mental retardation, epilepsy, coarse facial features and multiple organ anomalies that vary in severity depending upon the degree of defect and/or position in the pathway of affected gene. We clarified a mechanism of hyperphosphatasia, an elevated release of tissue nonspecific alkaline phosphatase (TNAP, GPI-AP), seen in some of the patients with IGDs such as hyperphosphatasia mental retardation syndrome or Mabry syndrome caused by mutation in genes in the later stage of GPI biosynthesis (J Biol Chem. 2012 vol. 287 p6318)
Here, we report four male patients with intellectual disabilities accompanied by seizures caused by the mutations in PIGA gene. These mutations were found by whole-exome sequencing using the Illumina HiSeq system. PIGA is X-linked gene which is involved in the first step of GPI biosynthesis pathway. These patients have germline hypomorphic mutations in PIGAgene and have completely different symptoms from patients with PNH, which is characterized by complement-mediated intravascular hemolysis.
Patient 1 had a hemizygous nonsense mutation, and was diagnosed with Ohtahara syndrome (early infantile epileptic encephalopathy with suppression burst) with multiple congenital anomalies. The nonsense mutation is leaky and caused a partial deficiency. Patient 2 had a maternally inherited hemizygous missense mutation and was diagnosed with early-onset West syndrome (a severe epilepsy syndrome characterized by infantile spasm with hypsarrhythmia). Patients 3 and 4 are brothers, had maternally inherited hemizygous missense mutation and were suffering from severe intellectual disabilities with seizures but not with any anomalies. Analysis by flow cytometry of patients’ blood cells revealed that all four patients showed decreased expression of GPI-APs on the granulocytes but not in erythrocytes or lymphocytes, suggesting that FACS analysis of granulocytes is useful to screen patients with IGD. Interestingly, the FACS analysis of the granulocytes from the mother of patients 3 and 4 showed mosaic pattern in CD16 expression. The mother seemed to have no neurological symptom, raising the possibility that contribution of GPI-AP-deficient cells to neuronal system does not occur or is only limited.
Although PNH and IGDs are different diseases, both are partial GPI deficiencies, the former affecting only hematopoietic cells, the latter having the hypomorphic mutations, which rescue the patients from lethality but cause the severe hematopoietic and developmental abnormalities, respectively.
Disclosures:
No relevant conflicts of interest to declare.
A novel
PCDH19
missense mutation, c.812G>A (p.Gly271Asp), identified using whole‐exome sequencing in a Chinese family with epilepsy female restricted mental retardation syndrome
