Novel PKLR missense mutation (A300P) causing pyruvate kinase deficiency in an Omani Kindred - PK deficiency masquerading as Congenital Dyserythropoietic Anemia.

A 15 year child is presented with transfusion dependent chronic anemia. The clinical and laboratory features suggested a chronic nonspherocytic hemolytic anemia (CNSHA) with bone marrow suggestive of congenital dyserythropoietic anemia (CDA). DNA studies revealed the underlying novel mutation in the PKLR gene responsible for pyruvate kinase deficiency.

Autosomal Recessive Congenital Dyserythropoietic Anemia Type III Is Caused By Mutations in the Centralspindlin RACGAP1 Component

An autosomal dominant form of congenital dyserythropoietic anemia type III (CDA III) is caused by a missense mutation in the KIF23 gene whose protein product, mitotic kinesin-like protein (MKLP1), is part of the centralspindlin complex involved in cytokinesis. Several case reports suggested the existence of an autosomal recessive inheritance form of CDA III so far not genetically characterized. By means of whole exome sequencing in a Spanish CDA III family with healthy parents, we identified in the male proband a novel homozygous missense mutation p.Pro432Ser in the RACGAP1 gene, which encodes for the RACGAP1 protein (Rac GTPase-activating protein 1, also known as MgcRacGAP or CYK-4), the partner of MKLP1 in the centralspindlin complex. A second CDA III Spanish patient has a different rare and novel homozygous missense mutation, p.Thr220Ala, in the RACGAP1 gene. Both patients presented with macrocytic anemia, aberrant multinucleated erythroblasts in the bone marrow typically seen in CDA III cases, no iron overload and skull defects secondary to severe anemia. Silencing of RACGAP1 using siRNA in HeLa cells mimics the cytokinesis defect observed in the bone marrow of our patients. Both mutations disrupt normal cytokinesis and alter the GTPase balance in patients' cells. We conclude that the autosomal recessive form of CDA type III is caused by mutations in the RACGAP1 gene, encoding for RACGAP1 protein, which is the partner of MKLP1 in the centralspindlin complex critical for cytokinesis and now both proteins are associated with CDA type III. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.

A common SEC23B missense mutation in congenital dyserythropoietic anemia type II leads to growth restriction and symptoms of chronic pancreatitis in mice

In humans, loss-of-function mutations in SEC23B result in congenital dyserythropoietic anemia type II (CDAII). Complete deficiency of Sec23b in mice leads to perinatal death caused by massive degeneration of professional secretory tissues with no CDAII phenotype. Functions of SEC23B in postnatal mice are unclear. In this study, we generated mice with the E109K mutation (Sec23bki/ki), the most common CDAII missense mutation. The E109K mutation leads to decreased SEC23B protein level, and results in mislocalization of SEC23B. However, Sec23bki/ki mice showed no obvious abnormalities. Hemizygous (Sec23bki/ko) mice exhibit a partial lethal phenotype, with half of these mice survive past weaning. Sec23bki/ko mice had chronic pancreatic histology changes such as interstitial fibrosis, white blood cell infiltration and exocrine insufficiency. Increased ER stress was found in Sec23bki/ko pancreas, associated with increased apoptosis. Moreover, Sec23bki/ko mice exhibited severe growth retardation accompanied by growth hormone (GH) insensitivity, reminiscent of the Laron syndrome. Interestingly, mice with hepatocyte-specific Sec23b deletion grow normally, suggesting non-liver origin of the phenotype. Inflammation associated with chronic pancreatic deficiency may explain GH insensitivity in Sec23bki/ko mice. Our results indicate that phenotype severities are linked to the residual functions of SEC23B in mice, further demonstrating a critical role of SEC23B in pancreatic acinar function in adult mice. The Sec23bki/ko mice provide a novel model of chronic pancreatitis and growth retardation.