In an investigation of a family with two affected siblings, a frameshift mutation in SEC31A was identified as a candidate causal mutation, causing a novel neurodevelopmental disorder with spastic quadriplegia, optic atrophy, seizures, and structural brain anomalies. Both siblings died by the age of four. SEC31A is one of the five human COP-II (coat protein complex II) proteins, which enable extrusion and secretion of vesicles from the endoplasmic reticululm.
The human gene SEC31A has not been introduced to Drosophila.
There is a single orthologous gene in Drosophila, Sec31, for which RNAi targeting constructs and P-element alleles have been made. Sec31 is a member of the COPII complex (gene group: FBgg0000116) , where it acts in a heterotetramer with Sec31 to form the outer cage of ER vesicles undergoing anterograde transport to the Golgi.
Sec31 null mutation and ubiquitous RNAi knockdown are homozygous lethal. Neuron-specific knockdown causes larvae to develop normally until the third instar stage, where the majority cease to develop and eventually die. The brains of these larvae are very fragile and easily disintegrate during dissection.
[updated November 2019 by FlyBase; FBrf0222196]
[HALPERIN-BIRK SYNDROME; HLBKS](https://omim.org/entry/618651)
[SEC31 HOMOLOG A, COPII COAT COMPLEX COMPONENT; SEC31A](https://omim.org/entry/610257)
A neurological disorder characterised by brain structural defects, spastic quadriplegia with multiple contractures, profound developmental delay and convulsions as well as dysmorphism, cataract and optic nerve atrophy, which is lethal by the age of 4. (Halperin et al. 2019, FBrf0241565)
Microcephaly, agenesis of the corpus callosum, and mildly impaired intrauterine growth retardation were apparent in utero by ultrasound. After birth, the patients had failure to thrive and subsequently had almost no developmental progress. They had no visual or verbal communication, were unable to walk, had only minimal nonpurposeful movements, and had spastic quadriplegia with hypertonia, hyperreflexia, and contractures. Other features included pseudobulbar palsy associated with gastroesophageal reflux and recurrent aspiration, congenital cataracts, optic atrophy, and hearing impairment. Both developed focal and generalized seizures soon after birth, and EEG showed disorganized background activity with sharp spike-wave discharges. Dysmorphic features included abnormal skull shape, pointed triangular face, micrognathia, high-arched palate, thick lips, long eyelashes, and dislocation of the hips. One patient had clubfoot, congenital diaphragmatic hernia, umbilical and inguinal hernia, and perimembranotic ventricular septal defect (VSD). Brain imaging in both showed severe structural abnormalities, including semilobar holoprosencephaly, agenesis of the corpus callosum, enlarged ventricles, and colpocephaly. [from MIM:618651, 2019.11.06]
Exhibits autosomal recessive inheritance. In the parents of affected children, a frameshift mutation in SEC31A leads to early truncation of the protein; the transcript is degraded via nonsense-mediated decay. Carrier parents expressed SEC31A mRNA at roughly half the level of non-carrier family members. (Halperin et al. 2019, FBrf0241565)
In 2 siblings with NEDSOB, born of consanguineous parents, Halperin et al. 2019 (FBrf0241565) identified a homozygous frameshift mutation in the SEC31A gene. The mutation, which was found by a combination of homozygosity mapping and whole-exome sequencing, segregated with the disorder in the family. [from MIM:618651, 2019.11.06]
The highly conserved COP-II proteins are recruited in a ordered pattern to induce curvature of a membrane, expand and shape it, capture target molecules, and break away to form a contained vesicle. The Sec13/Sec31 tetramer drives membrane bending from the outside of the vesicle. (Lord et al. 2013, pubmed:23378591)
Many human genes to one Drosophila gene; Hsap\SEC31B is also an ortholog for Sec31.
High-ranking ortholog of both Hsap\SEC31A and SEC31B.
