HICF2: COG7 Y500C

HIFC2 entry with custom annotation ported to Michelanglo.

The mutation Y500C is present in ExAC 39 times. rs146603761. But the patient is homozygous. Also there is a link between this gene and the disease. To do: what is SEC23B relative to COG7?

Structure

Structure generated with iTasser. Confidence is fairly low for some bits, but the SS is consistent and this is just shy of a helix.
However, Consurf server (conservation mapped as B factor) shows that the AA and the nearby region is very conserved.

As it is not a cystosolic protein it could be a cysteine disulfide issue (two are closeby).
Too little is know to determine why it is pathogenic.

It's marked as homozygous. Recessive (homozygous)

Protein role

This protein is part of Conserved_oligomeric_Golgi_complex. wiki This protein is required for normal Golgi morphology.
"Mutations in this gene are associated with the congenital disorder of glycosylation type IIe" pRec is 1. Patient is homozygous. article about glyco

Disease

The disease is Congenital dyserythropoietic anaemia From [this article)[http://cshperspectives.cshlp.org/content/3/9/a005371.full]:

Another example showing unpredictable functional consequences is also seen in two disorders caused by mutations in the family of COPII coat protein complexes, SEC23A and SEC23B (Lang et al. 2006; Bianchi et al. 2009). Mutations in SEC23A cause the cranio-lenticulo-sutural dysplasia syndrome and affect facial development (Boyadjiev et al. 2006). In zebrafish, positional cloning mapped the defect of a malformed craniofacial skeleton, kinked pectoral fins and a short body length to the homolog of sec23b. The mutant fish also showed accumulation of ECM components including type II collagen in the ER (Lang et al. 2006). Mice mutated in the transcription factor BBF2H7 that activates Sec23A transcription have a similar phenotype to GMAP210-deficient mice including abnormal chondrogenesis and accumulation of collagen II and cartilage oligomeric matrix protein in the ER. Introduction of Sec23A into chondrocytes normalized the secretion of matrix components (Stagg et al. 2008; Saito et al. 2009).

The mutant form of SEC23A poorly recruits the SEC13-SEC31 complex, inhibiting vesicle formation. Surprisingly, this effect is modulated by the SAR1 GTPase paralog used in the reaction, indicating distinct affinities of the two human SAR1 paralogs for the SEC13–SEC31 complex. Patient cells accumulate numerous tubular cargo-containing ER exit sites devoid of observable membrane coat, likely representing an intermediate step in COPII vesicle formation (Fromme et al. 2007).

In contrast, SEC23B mutations cause a completely different glycosylation disorder called congenital dyserythropoietic anemia or HEMPAS (Schwarz et al. 2009). These patients have poor erythropoiesis generating bi- and multinucleated erythroblasts in bone marrow, suggesting abnormal cytokinesis (Denecke and Marquardt 2009). In peripheral red blood cells, proteins and glycolipids are incompletely glycosylated (Fukuda 1990). This leads to a progressive splenomegaly, gallstones, and iron overload potentially with liver cirrhosis or cardiac failure. Knockdown of SEC23B via shRNA mimics the defective cytokinesis, and zebrafish morphants have abnormal enrythrocyte development (Bianchi et al. 2009; Schwarz et al. 2009). Surprisingly analysis of one family showed that heterozygous parents had detectable abnormalities in erythrocyte membrane glycans, but a healthy child was completely normal, thus suggesting the presence of a subclinical haploinsufficiency (Zdebska et al. 2002).

Ubiquitination

The residue next to it. K499 is ubiquinated in https://www.phosphosite.org/proteinAction.action?id=23543&showAllSites=true