* 609894

UNC13, C. ELEGANS, HOMOLOG OF, A; UNC13A


Alternative titles; symbols

MUNC13-1
KIAA1032


HGNC Approved Gene Symbol: UNC13A

Cytogenetic location: 19p13.11     Genomic coordinates (GRCh38): 19:17,601,327-17,688,343 (from NCBI)


TEXT

▼ Description

Proteins of the UNC13 family, such as UNC13A, are diacylglycerol and phorbol ester receptors with ligand affinities similar to those of protein kinase C (see PRKCA; 176960). Rodent Unc13a is a presynaptic protein with an essential role in synaptic vesicle priming (Rossner et al., 2004).


▼ Cloning and Expression

By sequencing clones obtained from a size-fractionated fetal brain cDNA library, Kikuno et al. (1999) cloned UNC13A, which they designated KIAA1032. The 3-prime UTR of the UNC13A transcript contains several repetitive elements. The deduced 986-amino acid protein shares 96% amino acid identity with its rat homolog, Munc13-1. RT-PCR ELISA detected high UNC13A expression in adult brain and in in several specific brain regions. Expression was lower in fetal brain and lowest in adult spleen, testis, pancreas, ovary, heart, and lung. No expression was detected in adult liver, skeletal muscle, and kidney or in fetal liver.


▼ Mapping

By radiation hybrid analysis, Kikuno et al. (1999) mapped the UNC13A gene to chromosome 19.


▼ Gene Function

By coimmunoprecipitation analysis of rat brain proteins, Ohtsuka et al. (2002) found that Cast (ERC2; 617250) formed a ternary complex with the cytomatrix at the active zone (CAZ) complex proteins Rim1 (RIMS; 606629) and Munc13-1. Mutation analysis revealed that the C-terminal PDZ-binding motif of Cast bound to the PDZ domain of Rim1. Cast was at least partly responsible for synaptic localization of Rim1. Cast bound Munc13-1 indirectly through Rim1, and it also interacted with the synaptic protein Bassoon (BSN; 604020).

Takao-Rikitsu et al. (2004) found that Cast, Rim1, Munc13-1, Bassoon, and Piccolo (PCLO; 604918) formed the CAZ protein complex in rat brain. Their findings suggested that CAST serves as a key component of the CAZ structure and is involved in neurotransmitter release by binding other CAZ proteins.


▼ Molecular Genetics

For discussion of a possible association between congenital myasthenic syndrome (see, e.g., CMS1A, 601462) and variation in the UNC13A gene, see 609894.0001.

▼ Animal Model

Rossner et al. (2004) examined amyloid precursor protein (APP; 104760) processing in mice deficient in Munc13-1 and in transgenic mice overexpressing a mutant Munc13-1 unable to bind diacylglycerol or phorbol esters. Since both mutant animals die within 5 hours of birth, Rossner et al. (2004) analyzed brains of newborn mice and organotypic brain slice cultures established from newborn mice. Both groups of mutant mice had a specific impairment in the alpha-secretase (CTSB; 116810) pathway of App processing. Rossner et al. (2004) also found that phorbol ester-stimulated App secretion was much less pronounced in brain slices of mutant mice compared with those of wildtype mice.


▼ ALLELIC VARIANTS ( 1 Selected Example):

.0001  VARIANT OF UNKNOWN SIGNIFICANCE

UNC13A, GLN102TER   
dbSNP:rs1057517677 RCV000412639

This variant is classified as a variant of unknown significance because its contribution to congenital myasthenic syndrome (see, e.g., CMS1A, 601462) has not been confirmed.

In a Native American girl with fatal presynaptic congenital myasthenic syndrome, Engel et al. (2016) identified a homozygous c.304C-T transition (c.304C-T, NM_001080421.2) in the UNC13A gene, resulting in a gln102-to-ter (Q102X) substitution. The variant, which was found by whole-exome sequencing and confirmed by Sanger sequencing, was not present in the ExAC database. The mutation segregated with the disorder in the family. Functional studies of the variant were not performed, but it was predicted to result in a complete loss of function. The patient, who was born prematurely at 32 weeks' gestation, presented at birth with hypotonia, respiratory insufficiency, and poor feeding. She had dysmorphic facial features, including microcephaly, high forehead, frontotemporal narrowing, wide nasal bridge, small jaw, and high-arched palate. She also had contractures, no voluntary eye movements, and abnormal EEG with nearly continuous multifocal sharp waves. There was no electric response to photic or auditory stimulation. EMG showed low compound muscle action potentials (CMAPs) and decremental response upon repetitive nerve stimulation. Analysis of the neuromuscular junction showed reduced spontaneous miniature endplate potential (MEPP) frequency and amplitude, and decreased numbers of readily releasable quanta. Skeletal muscle biopsy showed type 2 fiber atrophy and type 1 fiber hypertrophy. At age 21 months, she could not sit up or speak; she died of respiratory failure at age 50 months. Engel et al. (2016) suggested that loss of UNC13A function would inhibit cholinergic transmission at the neuromuscular junction and glutamatergic transmission in the brain.


▼ REFERENCES

  1. Engel, A. G., Selcen, D., Shen, X.-M., Milone, M., Harper, C. M. Loss of MUNC13-1 function causes microcephaly, cortical hyperexcitability, and fatal myasthenia. Neurol. Genet. 2: e105, 2016. Note: Electronic Article. [PubMed: 27648472, images, related citations] [Full Text]

  2. Kikuno, R., Nagase, T., Ishikawa, K., Hirosawa, M., Miyajima, N., Tanaka, A., Kotani, H., Nomura, N., Ohara, O. Prediction of the coding sequences of unidentified human genes. XIV. The complete sequences of 100 new cDNA clones from brain which code for large proteins in vitro. DNA Res. 6: 197-205, 1999. [PubMed: 10470851, related citations]

  3. Ohtsuka, T., Takao-Rikitsu, E., Inoue, E., Inoue, M., Takeuchi, M., Matsubara, K., Deguchi-Tawarada, M., Satoh, K., Morimoto, K., Nakanishi, H., Takai, Y. CAST: a novel protein of the cytomatrix at the active zone of synapses that forms a ternary complex with RIM1 and Munc13-1. J. Cell Biol. 158: 577-590, 2002. [PubMed: 12163476, images, related citations] [Full Text]

  4. Rossner, S., Fuchsbrunner, K., Lange-Dohna, C., Hartlage-Rubsamen, M., Bigl, V., Betz, A., Reim, K., Brose, N. Munc13-1-mediated vesicle priming contributes to secretory amyloid precursor protein processing. J. Biol. Chem. 279: 27841-27844, 2004. [PubMed: 15123597, related citations] [Full Text]

  5. Takao-Rikitsu, E., Mochida, S., Inoue, E., Deguchi-Tawarada, M., Inoue, M., Ohtsuka, T., Takai, Y. Physical and functional interaction of the active zone proteins, CAST, RIM1, and Bassoon, in neurotransmitter release. J. Cell Biol. 164: 301-311, 2004. [PubMed: 14734538, images, related citations] [Full Text]


Contributors:
Patricia A. Hartz - updated : 12/15/2016
Cassandra L. Kniffin - updated : 12/13/2016
Creation Date:
Patricia A. Hartz : 2/17/2006
Edit History:
mgross : 12/15/2016
carol : 12/14/2016
ckniffin : 12/13/2016
mgross : 02/17/2006

* 609894

UNC13, C. ELEGANS, HOMOLOG OF, A; UNC13A


Alternative titles; symbols

MUNC13-1
KIAA1032


HGNC Approved Gene Symbol: UNC13A

Cytogenetic location: 19p13.11     Genomic coordinates (GRCh38): 19:17,601,327-17,688,343 (from NCBI)


TEXT

Description

Proteins of the UNC13 family, such as UNC13A, are diacylglycerol and phorbol ester receptors with ligand affinities similar to those of protein kinase C (see PRKCA; 176960). Rodent Unc13a is a presynaptic protein with an essential role in synaptic vesicle priming (Rossner et al., 2004).


Cloning and Expression

By sequencing clones obtained from a size-fractionated fetal brain cDNA library, Kikuno et al. (1999) cloned UNC13A, which they designated KIAA1032. The 3-prime UTR of the UNC13A transcript contains several repetitive elements. The deduced 986-amino acid protein shares 96% amino acid identity with its rat homolog, Munc13-1. RT-PCR ELISA detected high UNC13A expression in adult brain and in in several specific brain regions. Expression was lower in fetal brain and lowest in adult spleen, testis, pancreas, ovary, heart, and lung. No expression was detected in adult liver, skeletal muscle, and kidney or in fetal liver.


Mapping

By radiation hybrid analysis, Kikuno et al. (1999) mapped the UNC13A gene to chromosome 19.


Gene Function

By coimmunoprecipitation analysis of rat brain proteins, Ohtsuka et al. (2002) found that Cast (ERC2; 617250) formed a ternary complex with the cytomatrix at the active zone (CAZ) complex proteins Rim1 (RIMS; 606629) and Munc13-1. Mutation analysis revealed that the C-terminal PDZ-binding motif of Cast bound to the PDZ domain of Rim1. Cast was at least partly responsible for synaptic localization of Rim1. Cast bound Munc13-1 indirectly through Rim1, and it also interacted with the synaptic protein Bassoon (BSN; 604020).

Takao-Rikitsu et al. (2004) found that Cast, Rim1, Munc13-1, Bassoon, and Piccolo (PCLO; 604918) formed the CAZ protein complex in rat brain. Their findings suggested that CAST serves as a key component of the CAZ structure and is involved in neurotransmitter release by binding other CAZ proteins.


Molecular Genetics

For discussion of a possible association between congenital myasthenic syndrome (see, e.g., CMS1A, 601462) and variation in the UNC13A gene, see 609894.0001.

Animal Model

Rossner et al. (2004) examined amyloid precursor protein (APP; 104760) processing in mice deficient in Munc13-1 and in transgenic mice overexpressing a mutant Munc13-1 unable to bind diacylglycerol or phorbol esters. Since both mutant animals die within 5 hours of birth, Rossner et al. (2004) analyzed brains of newborn mice and organotypic brain slice cultures established from newborn mice. Both groups of mutant mice had a specific impairment in the alpha-secretase (CTSB; 116810) pathway of App processing. Rossner et al. (2004) also found that phorbol ester-stimulated App secretion was much less pronounced in brain slices of mutant mice compared with those of wildtype mice.


ALLELIC VARIANTS 1 Selected Example):

.0001  VARIANT OF UNKNOWN SIGNIFICANCE

UNC13A, GLN102TER    rs1057517677

This variant is classified as a variant of unknown significance because its contribution to congenital myasthenic syndrome (see, e.g., CMS1A, 601462) has not been confirmed.

In a Native American girl with fatal presynaptic congenital myasthenic syndrome, Engel et al. (2016) identified a homozygous c.304C-T transition (c.304C-T, NM_001080421.2) in the UNC13A gene, resulting in a gln102-to-ter (Q102X) substitution. The variant, which was found by whole-exome sequencing and confirmed by Sanger sequencing, was not present in the ExAC database. The mutation segregated with the disorder in the family. Functional studies of the variant were not performed, but it was predicted to result in a complete loss of function. The patient, who was born prematurely at 32 weeks' gestation, presented at birth with hypotonia, respiratory insufficiency, and poor feeding. She had dysmorphic facial features, including microcephaly, high forehead, frontotemporal narrowing, wide nasal bridge, small jaw, and high-arched palate. She also had contractures, no voluntary eye movements, and abnormal EEG with nearly continuous multifocal sharp waves. There was no electric response to photic or auditory stimulation. EMG showed low compound muscle action potentials (CMAPs) and decremental response upon repetitive nerve stimulation. Analysis of the neuromuscular junction showed reduced spontaneous miniature endplate potential (MEPP) frequency and amplitude, and decreased numbers of readily releasable quanta. Skeletal muscle biopsy showed type 2 fiber atrophy and type 1 fiber hypertrophy. At age 21 months, she could not sit up or speak; she died of respiratory failure at age 50 months. Engel et al. (2016) suggested that loss of UNC13A function would inhibit cholinergic transmission at the neuromuscular junction and glutamatergic transmission in the brain.


REFERENCES

  1. Engel, A. G., Selcen, D., Shen, X.-M., Milone, M., Harper, C. M. Loss of MUNC13-1 function causes microcephaly, cortical hyperexcitability, and fatal myasthenia. Neurol. Genet. 2: e105, 2016. Note: Electronic Article. [PubMed: 27648472] [Full Text: https://dx.doi.org/10.1212/NXG.0000000000000105]

  2. Kikuno, R., Nagase, T., Ishikawa, K., Hirosawa, M., Miyajima, N., Tanaka, A., Kotani, H., Nomura, N., Ohara, O. Prediction of the coding sequences of unidentified human genes. XIV. The complete sequences of 100 new cDNA clones from brain which code for large proteins in vitro. DNA Res. 6: 197-205, 1999. [PubMed: 10470851]

  3. Ohtsuka, T., Takao-Rikitsu, E., Inoue, E., Inoue, M., Takeuchi, M., Matsubara, K., Deguchi-Tawarada, M., Satoh, K., Morimoto, K., Nakanishi, H., Takai, Y. CAST: a novel protein of the cytomatrix at the active zone of synapses that forms a ternary complex with RIM1 and Munc13-1. J. Cell Biol. 158: 577-590, 2002. [PubMed: 12163476] [Full Text: http://jcb.rupress.org/cgi/pmidlookup?view=long&pmid=12163476]

  4. Rossner, S., Fuchsbrunner, K., Lange-Dohna, C., Hartlage-Rubsamen, M., Bigl, V., Betz, A., Reim, K., Brose, N. Munc13-1-mediated vesicle priming contributes to secretory amyloid precursor protein processing. J. Biol. Chem. 279: 27841-27844, 2004. [PubMed: 15123597] [Full Text: http://www.jbc.org/cgi/pmidlookup?view=long&pmid=15123597]

  5. Takao-Rikitsu, E., Mochida, S., Inoue, E., Deguchi-Tawarada, M., Inoue, M., Ohtsuka, T., Takai, Y. Physical and functional interaction of the active zone proteins, CAST, RIM1, and Bassoon, in neurotransmitter release. J. Cell Biol. 164: 301-311, 2004. [PubMed: 14734538] [Full Text: http://jcb.rupress.org/cgi/pmidlookup?view=long&pmid=14734538]


Contributors:
Patricia A. Hartz - updated : 12/15/2016
Cassandra L. Kniffin - updated : 12/13/2016
Creation Date:
Patricia A. Hartz : 2/17/2006
Edit History:
mgross : 12/15/2016
carol : 12/14/2016
ckniffin : 12/13/2016
mgross : 02/17/2006