Halperin-Birk syndrome

Last updated
Halpein-Birk syndrome
Other namesHLBKS
Specialty Neurodevelopmental
Symptoms Intrauterine growth retardation, developmental delay, spastic quadriplegia with profound contractures, dysmorphism, microcephaly and agenesis of the corpus callosum
Usual onsetCongenital
CausesSEC31 gene LOF mutation
Prognosis Early lethality

Halperin-Birk syndrome (HLBKS) is a rare autosomal recessive neurodevelopmental disorder caused by a null mutation in the SEC31A gene. Signs and symptoms include intrauterine growth retardation, marked developmental delay, spastic quadriplegia with profound contractures, dysmorphism, and optic nerve atrophy with no eye fixation. Brain MRI demonstrated microcephaly and agenesis of the corpus callosum. [1]

Contents

The syndrome was first described in 2019 by Dr. Daniel Halperin and Prof. Ohad Birk at the Morris Kahn Laboratory for Human Genetics, Ben Gurion University of the Negev.[ citation needed ]

Signs and symptoms

Source: [1]

Inheritance

Autosomal recessive inheritance Autosomal recessive - mini.svg
Autosomal recessive inheritance

Growth

Head & neck

Respiratory

Gastrointestinal

Skeletal

Muscle, soft tissues

Neurologic

Causes

Halperin-Birk syndrome describes a severe autosomal recessive neurodevelopmental disorder caused by a loss of function mutation in SEC31A, a component of the coat protein complex II (COP-II). SEC31A (transcript variant 1; NM_ 001318120), also known as KIAA0905 and SEC31-related protein A (SEC31L1), encodes the transport protein SEC31A, a 1220 amino acid protein that is highly conserved through evolution. It contains multiple WD repeats near the N-terminus and conserved proline-rich region in its C-terminal. [2] SEC31A is a component of the COPII protein complex, responsible for vesicle budding from the Endoplasmic Reticulum (ER). It has been demonstrated to be highly expressed in the notochord, optic tectum, otic vesicle, cleithrum, and fin during embryogenesis. [3] Its importance to neuronal and craniofacial development has been demonstrated mainly through its efficient coupling with SEC13 and the SEC23-SEC31A interface. Failure to recruit SEC31A results in severe secretion defects of procollagen, and an enlarged ER, in line with aberrant protein secretion.[ citation needed ]

Mechanism

The COP-II complex comprises five highly conserved proteins, among these SEC31A, creating small membrane vesicles that originate from the ER. [4] [5] Budding of these vesicles is essential in the cellular trafficking pathway, through which membrane and luminal cargo proteins are transported from their site of synthesis to other cellular compartments. [6] This machinery assembles hierarchically, driven by the initial recruitment and activation of the small GTPase SAR1, which exists in a soluble cytoplasmic form when in its GDP-bound state. [7] SAR1 is promoted by SEC12, a membrane-bound GEF that catalyzes GDP/GTP exchange. [8] Once tightly anchored into the ER membrane, the active GTP-bound SAR1 recruits the SEC23-SEC24 heterodimer to form the inner "pre-budding" complex, capable of engaging cargo through interactions between SEC24 and multiple ER export motifs. [9] [10] Finally, the SEC13–SEC31A hetero-tetramer is recruited to promote coat polymerization, membrane curvature, and eventually membrane fission. [11] [12] With the full complement of the COP-II complex, the extruded membrane is separated from the ER membrane to form an intact vesicle. [13]

Most mammalian COP-II complex subunits have one or more paralogues with partially redundant functions, as the loss of selected copies often results in a genetic disease. [14] The mammalian repertoire consists of two SAR1 paralogs, SAR1A and SAR1B; two SEC23 paralogs, SEC23A and SEC23B; four SEC24 paralogs, SEC24A, SEC24B, SEC24C, and SEC24D; a single SEC13 and two SEC31 paralogs: SEC31A, comprising part of the SEC13/SEC31 hetero-tetramer, and SEC31B. The repertoire of COP-II paralogs available in mammals could contribute to a wide variety of COP-II coats, thus facilitating selective cargo transport in a tissue-specific manner. Alternative splicing could further contribute to the COP-II vesicle and cargo selection diversity. [15]

Associated diseases/phenotypes with mutations in the COP-II complex genes described to date (2021)
Yeast COP-IIMammalian COP-IIOrganismAssociated disease/phenotypesOMIM
SAR1pSAR1A
SAR1BHumanChylomicron retention (CMRD)/Anderson's disease 246700
SEC23pSEC23AHumanCranio-lenticulo-sutural dysplasia (CLSD) 607812
ZebrafishSkeletal and craniofacial development defects
SEC23BHumanCongenital dyserythropoietic anemia type II (CDAII) 610512
ZebrafishAberrant erythrocyte development
SEC24pSEC24AArabidopsis thalianaSecretory and Golgi proteins accumulate in ER
SEC24BMiceNeural tube defects and craniorachischisis
SEC24CMiceEmbryonic lethality
SEC24DHumanOsteogenesis imperfecta-like syndrome 607186
ZebrafishCraniofacial dysmorphology, defects in trafficking of ECM proteins including type II collagen
MedakaSkeletal and facial development defects
MiceEarly embryonic lethality
SEC13pSEC13ZebrafishDefects in proteoglycan deposition cause CLSD-like phenotype
SEC31pSEC31AHumanHalperin-Birk syndrome 618615
SEC31B

Molecular genetics

CRISPR/Cas9-mediated knockdown of the SEC31A gene in human SH-SY5Y neuroblastoma cells resulted in the failure of the cells to expand to generate viable clones. In addition, knockdown of the gene in HEK293 cells increased susceptibility to ER stress compared to controls. These results suggest that enhanced ER stress response is likely part of the molecular mechanism of the human disease. [1]

Diagnosis

There is no specific test to diagnose HLBKS other than exome/genome sequencing. [1]

Treatment

Currently, there are no genetic therapies specifically targeting the underlying cause of HLBKS. However, following the identification of the syndrome, a preimplantation genetic diagnosis (PGD) can be offered when one or both genetic parents are carriers of a mutation in this gene. [1]

Research

Animal model

In-vivo C. elegans experiments have demonstrated that SEC31A-deficient mutants are embryonically lethal due to various developmental defects. [16] Halperin et al. (2019) found that complete loss of Sec31a in Drosophila was embryonically lethal and associated with eye and brain development defects, consistent with abnormal neurodevelopment. [1]

Related Research Articles

<span class="mw-page-title-main">Endoplasmic reticulum</span> Cell organelle that synthesizes, folds and processes proteins

The endoplasmic reticulum (ER) is a part of a transportation system of the eukaryotic cell, and has many other important functions such as protein folding. It is a type of organelle made up of two subunits – rough endoplasmic reticulum (RER), and smooth endoplasmic reticulum (SER). The endoplasmic reticulum is found in most eukaryotic cells and forms an interconnected network of flattened, membrane-enclosed sacs known as cisternae, and tubular structures in the SER. The membranes of the ER are continuous with the outer nuclear membrane. The endoplasmic reticulum is not found in red blood cells, or spermatozoa.

<span class="mw-page-title-main">Golgi apparatus</span> Cell organelle that packages proteins for export

The Golgi apparatus, also known as the Golgi complex, Golgi body, or simply the Golgi, is an organelle found in most eukaryotic cells. Part of the endomembrane system in the cytoplasm, it packages proteins into membrane-bound vesicles inside the cell before the vesicles are sent to their destination. It resides at the intersection of the secretory, lysosomal, and endocytic pathways. It is of particular importance in processing proteins for secretion, containing a set of glycosylation enzymes that attach various sugar monomers to proteins as the proteins move through the apparatus.

Protein targeting or protein sorting is the biological mechanism by which proteins are transported to their appropriate destinations within or outside the cell. Proteins can be targeted to the inner space of an organelle, different intracellular membranes, the plasma membrane, or to the exterior of the cell via secretion. Information contained in the protein itself directs this delivery process. Correct sorting is crucial for the cell; errors or dysfunction in sorting have been linked to multiple diseases.

<span class="mw-page-title-main">Vesicle (biology and chemistry)</span> Any small, fluid-filled, spherical organelle enclosed by a membrane

In cell biology, a vesicle is a structure within or outside a cell, consisting of liquid or cytoplasm enclosed by a lipid bilayer. Vesicles form naturally during the processes of secretion (exocytosis), uptake (endocytosis), and the transport of materials within the plasma membrane. Alternatively, they may be prepared artificially, in which case they are called liposomes. If there is only one phospholipid bilayer, the vesicles are called unilamellar liposomes; otherwise they are called multilamellar liposomes. The membrane enclosing the vesicle is also a lamellar phase, similar to that of the plasma membrane, and intracellular vesicles can fuse with the plasma membrane to release their contents outside the cell. Vesicles can also fuse with other organelles within the cell. A vesicle released from the cell is known as an extracellular vesicle.

The Coat Protein Complex II, or COPII, is a group of proteins that facilitate the formation of vesicles to transport proteins from the endoplasmic reticulum to the Golgi apparatus or endoplasmic-reticulum–Golgi intermediate compartment. This process is termed anterograde transport, in contrast to the retrograde transport associated with the COPI complex. COPII is assembled in two parts: first an inner layer of Sar1, Sec23, and Sec24 forms; then the inner coat is surrounded by an outer lattice of Sec13 and Sec31.

<span class="mw-page-title-main">COPI</span> Protein complex

COPI is a coatomer, a protein complex that coats vesicles transporting proteins from the cis end of the Golgi complex back to the rough endoplasmic reticulum (ER), where they were originally synthesized, and between Golgi compartments. This type of transport is retrograde transport, in contrast to the anterograde transport associated with the COPII protein. The name "COPI" refers to the specific coat protein complex that initiates the budding process on the cis-Golgi membrane. The coat consists of large protein subcomplexes that are made of seven different protein subunits, namely α, β, β', γ, δ, ε and ζ.

<span class="mw-page-title-main">Randy Schekman</span> American cell biologist

Randy Wayne Schekman is an American cell biologist at the University of California, Berkeley, former editor-in-chief of Proceedings of the National Academy of Sciences and former editor of Annual Review of Cell and Developmental Biology. In 2011, he was announced as the editor of eLife, a new high-profile open-access journal published by the Howard Hughes Medical Institute, the Max Planck Society and the Wellcome Trust launching in 2012. He was elected to the National Academy of Sciences in 1992. Schekman shared the 2013 Nobel Prize for Physiology or Medicine with James Rothman and Thomas C. Südhof for their ground-breaking work on cell membrane vesicle trafficking.

<span class="mw-page-title-main">Brefeldin A</span> Chemical compound

Brefeldin A is a lactone antiviral produced by the fungus Penicillium brefeldianum. Brefeldin A inhibits protein transport from the endoplasmic reticulum to the golgi complex indirectly by preventing association of COP-I coat to the Golgi membrane. Brefeldin A was initially isolated with hopes to become an antiviral drug but is now primarily used in research to study protein transport.

TRAPP (TRAnsport Protein Particle) is a protein involved in particle transport between organelles.

<span class="mw-page-title-main">ADP ribosylation factor</span> Group of proteins

ADP ribosylation factors (ARFs) are members of the ARF family of GTP-binding proteins of the Ras superfamily. ARF family proteins are ubiquitous in eukaryotic cells, and six highly conserved members of the family have been identified in mammalian cells. Although ARFs are soluble, they generally associate with membranes because of N-terminus myristoylation. They function as regulators of vesicular traffic and actin remodelling.

<span class="mw-page-title-main">Vesicular transport adaptor protein</span>

Vesicular transport adaptor proteins are proteins involved in forming complexes that function in the trafficking of molecules from one subcellular location to another. These complexes concentrate the correct cargo molecules in vesicles that bud or extrude off of one organelle and travel to another location, where the cargo is delivered. While some of the details of how these adaptor proteins achieve their trafficking specificity has been worked out, there is still much to be learned.

The coatomer is a protein complex that coats membrane-bound transport vesicles. Two types of coatomers are known:

<span class="mw-page-title-main">Nucleoporin</span> Family of proteins that form the nuclear pore complex

Nucleoporins are a family of proteins which are the constituent building blocks of the nuclear pore complex (NPC). The nuclear pore complex is a massive structure embedded in the nuclear envelope at sites where the inner and outer nuclear membranes fuse, forming a gateway that regulates the flow of macromolecules between the cell nucleus and the cytoplasm. Nuclear pores enable the passive and facilitated transport of molecules across the nuclear envelope. Nucleoporins, a family of around 30 proteins, are the main components of the nuclear pore complex in eukaryotic cells. Nucleoporin 62 is the most abundant member of this family. Nucleoporins are able to transport molecules across the nuclear envelope at a very high rate. A single NPC is able to transport 60,000 protein molecules across the nuclear envelope every minute.

<span class="mw-page-title-main">SEC31A</span> Protein-coding gene in the species Homo sapiens

Protein transport protein Sec31A is a protein that in humans is encoded by the SEC31A gene.

<span class="mw-page-title-main">SEC24C</span> Protein-coding gene in the species Homo sapiens

Protein transport protein Sec24C is a protein that in humans is encoded by the SEC24C gene.

KDEL is a target peptide sequence in mammals and plants located on the C-terminal end of the amino acid structure of a protein. The KDEL sequence prevents a protein from being secreted from the endoplasmic reticulum (ER) and facilitates its return if it is accidentally exported.

<span class="mw-page-title-main">Cranio-lenticulo-sutural dysplasia</span> Medical condition

Cranio-lenticulo-sutural dysplasia is a neonatal/infancy disease caused by a disorder in the 14th chromosome. It is an autosomal recessive disorder, meaning that both recessive genes must be inherited from each parent in order for the disease to manifest itself. The disease causes a significant dilation of the endoplasmic reticulum in fibroblasts of the host with CLSD. Due to the distension of the endoplasmic reticulum, export of proteins from the cell is disrupted.

Unconventional protein secretion represents a manner in which the proteins are delivered to the surface of plasma membrane or extracellular matrix independent of the endoplasmic reticulum or Golgi apparatus. This includes cytokines and mitogens with crucial function in complex processes such as inflammatory response or tumor-induced angiogenesis. Most of these proteins are involved in processes in higher eukaryotes, however an unconventional export mechanism was found in lower eukaryotes too. Even proteins folded in their correct conformation can pass plasma membrane this way, unlike proteins transported via ER/Golgi pathway. Two types of unconventional protein secretion are these: signal-peptid-containing proteins and cytoplasmatic and nuclear proteins that are missing an ER-signal peptide (1).

SEC31 is a protein which in yeast promotes the formation of COPII transport vesicles from the Endoplasmic Reticulum (ER). The coat has two main functions, the physical deformation of the endoplasmic reticulum membrane into vesicles and the selection of cargo molecules.

Exomer is a heterotetrameric protein complex similar to COPI and other adaptins. It was first described in the yeast Saccharomyces cerevisiae. Exomer is a cargo adaptor important in transporting molecules from the Golgi apparatus toward the cell membrane. The vesicles it is found on are different from COPI vesicles in that they do not appear to have a "coat" or "scaffold" around them.

References

  1. 1 2 3 4 5 6 Halperin, Daniel; Kadir, Rotem; Perez, Yonatan; Drabkin, Max; Yogev, Yuval; Wormser, Ohad; Berman, Erez M.; Eremenko, Ekaterina; Rotblat, Barak; Shorer, Zamir; Gradstein, Libe (2019-03-01). "SEC31A mutation affects ER homeostasis, causing a neurological syndrome". Journal of Medical Genetics. 56 (3): 139–148. doi:10.1136/jmedgenet-2018-105503. ISSN   0022-2593. PMID   30464055. S2CID   53717389.
  2. ↑ Tang, Bor Luen; Zhang, Tao; Low, Delphine Y.H.; Wong, Ee Tsin; Horstmann, Heinrich; Hong, Wanjin (May 2000). "Mammalian Homologues of Yeast Sec31p". Journal of Biological Chemistry. 275 (18): 13597–13604. doi: 10.1074/jbc.275.18.13597 . PMID   10788476.
  3. ↑ Sprague, J. (2006-01-01). "The Zebrafish Information Network: the zebrafish model organism database". Nucleic Acids Research. 34 (90001): D581–D585. doi:10.1093/nar/gkj086. ISSN   0305-1048. PMC   1347449 . PMID   16381936.
  4. ↑ Lord, C.; Ferro-Novick, S.; Miller, E. A. (2013-02-01). "The Highly Conserved COPII Coat Complex Sorts Cargo from the Endoplasmic Reticulum and Targets It to the Golgi". Cold Spring Harbor Perspectives in Biology. 5 (2): a013367. doi:10.1101/cshperspect.a013367. ISSN   1943-0264. PMC   3552504 . PMID   23378591.
  5. ↑ Barlowe, C (June 2003). "Signals for COPII-dependent export from the ER: what's the ticket out?". Trends in Cell Biology. 13 (6): 295–300. doi:10.1016/S0962-8924(03)00082-5. PMID   12791295.
  6. ↑ Jensen, Devon; Schekman, Randy (2011-01-01). "COPII-mediated vesicle formation at a glance". Journal of Cell Science. 124 (1): 1–4. doi: 10.1242/jcs.069773 . ISSN   1477-9137. PMID   21172817. S2CID   36908436.
  7. ↑ Gürkan, Cemal; Stagg, Scott M.; LaPointe, Paul; Balch, William E. (October 2006). "The COPII cage: unifying principles of vesicle coat assembly". Nature Reviews Molecular Cell Biology. 7 (10): 727–738. doi:10.1038/nrm2025. ISSN   1471-0072. PMID   16990852. S2CID   20469113.
  8. ↑ Bielli, Anna; Haney, Charles J.; Gabreski, Gavin; Watkins, Simon C.; Bannykh, Sergei I.; Aridor, Meir (2005-12-19). "Regulation of Sar1 NH2 terminus by GTP binding and hydrolysis promotes membrane deformation to control COPII vesicle fission". Journal of Cell Biology. 171 (6): 919–924. doi:10.1083/jcb.200509095. ISSN   1540-8140. PMC   2171319 . PMID   16344311.
  9. ↑ Barlowe, Charles (August 2003). "Molecular Recognition of Cargo by the COPII Complex". Cell. 114 (4): 395–397. doi: 10.1016/S0092-8674(03)00650-0 . PMID   12941266. S2CID   13972413.
  10. ↑ Miller, Elizabeth A; Beilharz, Traude H; Malkus, Per N; Lee, Marcus C.S; Hamamoto, Susan; Orci, Lelio; Schekman, Randy (August 2003). "Multiple Cargo Binding Sites on the COPII Subunit Sec24p Ensure Capture of Diverse Membrane Proteins into Transport Vesicles". Cell. 114 (4): 497–509. doi: 10.1016/S0092-8674(03)00609-3 . PMID   12941277. S2CID   6247102.
  11. ↑ Stagg, Scott M.; Gürkan, Cemal; Fowler, Douglas M.; LaPointe, Paul; Foss, Ted R.; Potter, Clinton S.; Carragher, Bridget; Balch, William E. (2006-01-12). "Structure of the Sec13/31 COPII coat cage". Nature. 439 (7073): 234–238. Bibcode:2006Natur.439..234S. doi:10.1038/nature04339. ISSN   0028-0836. PMID   16407955. S2CID   2426465.
  12. ↑ Fath, Stephan; Mancias, Joseph D.; Bi, Xiping; Goldberg, Jonathan (June 2007). "Structure and Organization of Coat Proteins in the COPII Cage". Cell. 129 (7): 1325–1336. doi: 10.1016/j.cell.2007.05.036 . PMID   17604721. S2CID   10692166.
  13. ↑ Antonny, Bruno; Madden, David; Hamamoto, Susan; Orci, Lelio; Schekman, Randy (June 2001). "Dynamics of the COPII coat with GTP and stable analogues". Nature Cell Biology. 3 (6): 531–537. doi:10.1038/35078500. ISSN   1465-7392. PMID   11389436. S2CID   19851244.
  14. ↑ Zanetti, Giulia; Pahuja, Kanika Bajaj; Studer, Sean; Shim, Soomin; Schekman, Randy (January 2012). "COPII and the regulation of protein sorting in mammals". Nature Cell Biology. 14 (1): 20–28. doi:10.1038/ncb2390. ISSN   1465-7392. PMID   22193160. S2CID   2828521.
  15. ↑ Khoriaty, Rami; Vasievich, Matthew P.; Ginsburg, David (2012-07-05). "The COPII pathway and hematologic disease". Blood. 120 (1): 31–38. doi:10.1182/blood-2012-01-292086. ISSN   0006-4971. PMC   3390960 . PMID   22586181.
  16. ↑ Skop, Ahna R.; Liu, Hongbin; Yates, John; Meyer, Barbara J.; Heald, Rebecca (2004-07-02). "Dissection of the Mammalian Midbody Proteome Reveals Conserved Cytokinesis Mechanisms". Science. 305 (5680): 61–66. Bibcode:2004Sci...305...61S. doi:10.1126/science.1097931. ISSN   0036-8075. PMC   3679889 . PMID   15166316.
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