Mutagenetix > Incidental Mutation

Incidental Mutation 'B6584:Astn2'

627

Institutional Source

Beutler Lab

Gene Symbol

Astn2

Ensembl Gene

ENSMUSG00000028373

Gene Name

astrotactin 2

Synonyms

1d8, Astnl

Accession Numbers

Essential gene?

Probably non essential (E-score: 0.105) question?

Stock #

B6584 (G3) of strain supermodel

Quality Score

Status

Validated

Chromosome

Chromosomal Location

65299040-66322774 bp(-) (GRCm39)

Type of Mutation

missense

DNA Base Change (assembly)

C to T at 65910624 bp (GRCm39)

Zygosity

Heterozygous

Amino Acid Change

Valine to Methionine at position 403 (V403M)

Ref Sequence

ENSEMBL: ENSMUSP00000081540 (fasta)

Gene Model

predicted gene model for transcript(s): [ENSMUST00000068214] [ENSMUST00000084496]

AlphaFold

Q80Z10

Predicted Effect

probably benign
Transcript: ENSMUST00000068214
AA Change: V455M

PolyPhen 2 Score 0.226 (Sensitivity: 0.91; Specificity: 0.88)

SMART Domains

Protein: ENSMUSP00000065786
Gene: ENSMUSG00000028373
AA Change: V455M

Domain	Start	End	E-Value	Type
signal peptide	1	51	N/A	INTRINSIC
low complexity region	87	127	N/A	INTRINSIC
transmembrane domain	219	241	N/A	INTRINSIC
low complexity region	303	312	N/A	INTRINSIC
low complexity region	342	361	N/A	INTRINSIC
low complexity region	393	404	N/A	INTRINSIC
low complexity region	432	437	N/A	INTRINSIC
transmembrane domain	443	465	N/A	INTRINSIC
EGF_like	526	563	2.92e1	SMART
Blast:EGF_like	667	708	2e-18	BLAST
EGF_like	715	764	4.03e1	SMART
MACPF	864	1048	2.88e-55	SMART
FN3	1079	1191	2.41e0	SMART

Predicted Effect

probably damaging
Transcript: ENSMUST00000084496
AA Change: V403M

PolyPhen 2 Score 0.988 (Sensitivity: 0.73; Specificity: 0.96)

SMART Domains

Protein: ENSMUSP00000081540
Gene: ENSMUSG00000028373
AA Change: V403M

Domain	Start	End	E-Value	Type
signal peptide	1	51	N/A	INTRINSIC
low complexity region	87	127	N/A	INTRINSIC
transmembrane domain	219	241	N/A	INTRINSIC
low complexity region	303	312	N/A	INTRINSIC
low complexity region	341	352	N/A	INTRINSIC
low complexity region	380	385	N/A	INTRINSIC
transmembrane domain	391	413	N/A	INTRINSIC
EGF_like	474	511	2.92e1	SMART
Blast:EGF_like	615	656	2e-18	BLAST
EGF_like	663	712	4.03e1	SMART
MACPF	812	996	2.88e-55	SMART
FN3	1027	1139	2.41e0	SMART

Meta Mutation Damage Score

0.2148

Coding Region Coverage

1x: 85.5%
3x: 70.0%

Het Detection Efficiency

43.9%

Validation Efficiency

89% (133/150)

MGI Phenotype

FUNCTION: [Summary is not available for the mouse gene. This summary is for the human ortholog.] This gene encodes a protein that is expressed in the brain and may function in neuronal migration, based on functional studies of the related astrotactin 1 gene in human and mouse. A deletion at this locus has been associated with schizophrenia. Multiple transcript variants encoding different proteins have been found for this locus. [provided by RefSeq, May 2010]

Allele List at MGI

All alleles(1) : Gene trapped(1)

Other mutations in this stock

Total: 12 list
Gene	Ref	Var	Chr/Loc	Mutation	Predicted Effect	Zygosity
1700102H20Rik	C	T	17: 3,609,853 (GRCm39)		probably benign	Homo
Acadl	T	A	1: 66,887,632 (GRCm39)		probably benign	Het
Clcc1	C	T	3: 108,580,229 (GRCm39)	T302I	probably damaging	Homo
Hormad1	T	A	3: 95,478,007 (GRCm39)		probably benign	Homo
Resf1	C	T	6: 149,230,844 (GRCm39)	H1297Y	probably damaging	Het
Rnf213	C	T	11: 119,316,895 (GRCm39)	T1007I	probably damaging	Het
Rrh	T	C	3: 129,605,391 (GRCm39)	N239D	probably damaging	Homo
Samd4	A	C	14: 47,253,794 (GRCm39)	H86P	probably damaging	Homo
Slc27a2	T	C	2: 126,403,562 (GRCm39)	L195P	possibly damaging	Het
Srek1ip1	T	C	13: 104,953,882 (GRCm39)		probably benign	Het
Tars2	T	C	3: 95,649,462 (GRCm39)		probably null	Homo
Zfp37	A	T	4: 62,109,615 (GRCm39)	V521E	probably damaging	Het

Other mutations in Astn2

Allele	Source	Chr	Coord	Type	Predicted Effect	PPH Score
IGL00964:Astn2	APN	4	66,103,424 (GRCm39)	missense	unknown
IGL01657:Astn2	APN	4	65,570,186 (GRCm39)	missense	probably damaging	0.99
IGL01747:Astn2	APN	4	65,712,855 (GRCm39)	missense	probably benign	0.17
IGL02008:Astn2	APN	4	65,977,390 (GRCm39)	missense	probably damaging	1.00
IGL02215:Astn2	APN	4	66,184,471 (GRCm39)	missense	unknown
IGL02484:Astn2	APN	4	65,910,516 (GRCm39)	splice site	probably benign
IGL02494:Astn2	APN	4	65,910,585 (GRCm39)	missense	probably benign	0.23
IGL02792:Astn2	APN	4	65,563,058 (GRCm39)	missense	probably benign	0.32
IGL03248:Astn2	APN	4	65,664,530 (GRCm39)	splice site	probably benign
IGL03409:Astn2	APN	4	65,353,423 (GRCm39)	missense	possibly damaging	0.46
R0015:Astn2	UTSW	4	66,184,619 (GRCm39)	critical splice acceptor site	probably null
R0015:Astn2	UTSW	4	66,184,619 (GRCm39)	critical splice acceptor site	probably null
R0092:Astn2	UTSW	4	66,322,219 (GRCm39)	missense	unknown
R0245:Astn2	UTSW	4	65,712,795 (GRCm39)	missense	probably damaging	0.99
R0528:Astn2	UTSW	4	65,563,119 (GRCm39)	splice site	probably benign
R0586:Astn2	UTSW	4	66,103,379 (GRCm39)	missense	unknown
R0652:Astn2	UTSW	4	65,712,795 (GRCm39)	missense	probably damaging	0.99
R0880:Astn2	UTSW	4	65,566,567 (GRCm39)	missense	probably damaging	0.99
R0931:Astn2	UTSW	4	65,566,530 (GRCm39)	missense	probably damaging	0.99
R1353:Astn2	UTSW	4	66,184,572 (GRCm39)	missense	unknown
R1700:Astn2	UTSW	4	65,664,591 (GRCm39)	nonsense	probably null
R1934:Astn2	UTSW	4	65,353,426 (GRCm39)	missense	probably damaging	0.99
R2017:Astn2	UTSW	4	65,459,178 (GRCm39)	missense	probably damaging	0.99
R2101:Astn2	UTSW	4	65,499,923 (GRCm39)	nonsense	probably null
R2158:Astn2	UTSW	4	66,322,491 (GRCm39)	missense	unknown
R2907:Astn2	UTSW	4	65,563,093 (GRCm39)	missense	possibly damaging	0.92
R2923:Astn2	UTSW	4	65,832,010 (GRCm39)	missense	probably damaging	1.00
R2938:Astn2	UTSW	4	65,910,550 (GRCm39)	missense	possibly damaging	0.92
R3033:Astn2	UTSW	4	65,562,943 (GRCm39)	missense	probably damaging	1.00
R3933:Astn2	UTSW	4	66,322,192 (GRCm39)	missense	unknown
R4151:Astn2	UTSW	4	65,647,557 (GRCm39)	critical splice donor site	probably null
R4230:Astn2	UTSW	4	65,829,919 (GRCm39)	missense	probably damaging	0.99
R4497:Astn2	UTSW	4	66,037,300 (GRCm39)	intron	probably benign
R4717:Astn2	UTSW	4	65,562,991 (GRCm39)	missense	possibly damaging	0.86
R4844:Astn2	UTSW	4	65,562,967 (GRCm39)	missense	possibly damaging	0.90
R4928:Astn2	UTSW	4	65,647,644 (GRCm39)	missense	probably damaging	0.98
R5374:Astn2	UTSW	4	65,315,242 (GRCm39)	missense	probably damaging	0.96
R5442:Astn2	UTSW	4	65,500,023 (GRCm39)	missense	possibly damaging	0.86
R5694:Astn2	UTSW	4	65,868,375 (GRCm39)	missense	probably damaging	1.00
R5756:Astn2	UTSW	4	66,037,425 (GRCm39)	intron	probably benign
R5763:Astn2	UTSW	4	65,647,568 (GRCm39)	missense	probably benign	0.14
R6089:Astn2	UTSW	4	65,712,810 (GRCm39)	missense	probably damaging	0.96
R6990:Astn2	UTSW	4	65,910,540 (GRCm39)	missense	possibly damaging	0.82
R7304:Astn2	UTSW	4	66,103,612 (GRCm39)	missense	unknown
R7325:Astn2	UTSW	4	65,460,906 (GRCm39)	missense	probably benign	0.33
R7356:Astn2	UTSW	4	66,103,503 (GRCm39)	missense	unknown
R7414:Astn2	UTSW	4	65,459,193 (GRCm39)	missense	possibly damaging	0.85
R7755:Astn2	UTSW	4	65,712,795 (GRCm39)	missense	probably damaging	0.99
R7887:Astn2	UTSW	4	65,563,103 (GRCm39)	missense	possibly damaging	0.51
R8027:Astn2	UTSW	4	65,459,208 (GRCm39)	missense	possibly damaging	0.86
R8046:Astn2	UTSW	4	66,184,587 (GRCm39)	nonsense	probably null
R8188:Astn2	UTSW	4	65,977,418 (GRCm39)	missense	unknown
R8271:Astn2	UTSW	4	65,910,663 (GRCm39)	missense	unknown
R8274:Astn2	UTSW	4	65,570,098 (GRCm39)	critical splice donor site	probably null
R8505:Astn2	UTSW	4	65,299,825 (GRCm39)	missense	unknown
R8815:Astn2	UTSW	4	65,830,834 (GRCm39)	missense	possibly damaging	0.96
R8989:Astn2	UTSW	4	65,499,890 (GRCm39)	missense	possibly damaging	0.53
R9013:Astn2	UTSW	4	65,910,584 (GRCm39)	missense	probably benign	0.23
R9127:Astn2	UTSW	4	66,322,164 (GRCm39)	missense	unknown
R9255:Astn2	UTSW	4	65,563,085 (GRCm39)	nonsense	probably null
R9297:Astn2	UTSW	4	65,460,960 (GRCm39)	missense	possibly damaging	0.85
R9320:Astn2	UTSW	4	66,322,386 (GRCm39)	missense	unknown
R9349:Astn2	UTSW	4	66,184,492 (GRCm39)	missense	unknown
R9399:Astn2	UTSW	4	65,664,588 (GRCm39)	missense	possibly damaging	0.71
R9572:Astn2	UTSW	4	65,299,872 (GRCm39)	missense	unknown
R9573:Astn2	UTSW	4	65,566,591 (GRCm39)	missense	probably benign	0.08
R9674:Astn2	UTSW	4	65,460,963 (GRCm39)	missense	probably damaging	0.98
R9722:Astn2	UTSW	4	65,831,978 (GRCm39)	missense	probably benign	0.33

Nature of Mutation

DNA sequencing using the SOLiD technique identified a G to A transition at position 1477 of the Astn2 transcript in exon 6 of 23 total exons. Multiple transcripts of the Astn2 gene are displayed on Ensembl. The mutated nucleotide causes a valine to methionine substitution at amino acid 455 of the encoded protein using Genbank NM_207109.2. The mutation has been confirmed by DNA sequencing using the Sanger method (Figure 1).

Protein Function and Prediction

The Astn2 gene encodes a transmembrane protein that is most similar to Astrotactin 1 (ASTN1) with 48% identity and 65% homology overall (1). Like Astn1, Astn2 is a vertebrate-specific gene and hypothesized to be a neuronal cell adhesion molecule. Two isoforms of Astn2 exist, a larger splice variant isoform b that expresses a protein of 1352 amino acids and isoform a, which encodes a 1300 amino acid protein with a shorter N-terminus (Figure 1). Due to an alternative methionine start site, ASTN2 isoforms have been reported to encode proteins containing 1132 residues and 1079 residues with the shorter isoform lacking exon 5 of 24 total exons. Western blot analysis using an antibody specific to ASTN2 supports these sizes (1). The 1079 amino acid form of ASTN2 contains a signal sequence, a transmembrane domain at residues 175-195, three epidermal growth factor-like (EGF) repeats (residues 250-290, 392-436 and 439-491), a membrane attack complex/Perforin (MACPF) domain located at amino acids 591-723, a fibronectin type III (FNIII) domain at residues 806-928 and five N-linked glycosylation sites. The alternatively spliced exon does not contain any conserved domains (1). The 1352 amino acid protein is predicted to contain an extra N-terminal transmembrane domain (Uniprot Q80Z10 ). A genome-wide association (GWA) study identified ASTN2 as a risk gene in deficit hyperactivity disorder (ADHD) (2), while copy number variants in ASTN2 are associated with autism and schizophrenia (3;4).

The V455M alteration occurs in the second transmembrane domain for the 1352 amino acid protein and is not predicted to change the topology according to the PredictProtein tool.

References

1. Wilson, P. M., Fryer, R. H., Fang, Y., and Hatten, M. E. (2010) Astn2, a Novel Member of the Astrotactin Gene Family, Regulates the Trafficking of ASTN1 during Glial-Guided Neuronal Migration. J. Neurosci.. 30, 8529-8540.

2. Lesch, K. P., Timmesfeld, N., Renner, T. J., Halperin, R., Roser, C., Nguyen, T. T., Craig, D. W., Romanos, J., Heine, M., Meyer, J., Freitag, C., Warnke, A., Romanos, M., Schafer, H., Walitza, S., Reif, A., Stephan, D. A., and Jacob, C. (2008) Molecular Genetics of Adult ADHD: Converging Evidence from Genome-Wide Association and Extended Pedigree Linkage Studies. J. Neural Transm.. 115, 1573-1585.

3. Vrijenhoek, T., Buizer-Voskamp, J. E., van der Stelt, I., Strengman, E., Genetic Risk and Outcome in Psychosis (GROUP) Consortium, Sabatti, C., Geurts van Kessel, A., Brunner, H. G., Ophoff, R. A., and Veltman, J. A. (2008) Recurrent CNVs Disrupt Three Candidate Genes in Schizophrenia Patients. Am. J. Hum. Genet.. 83, 504-510.

4. Glessner, J. T., Wang, K., Cai, G., Korvatska, O., Kim, C. E., Wood, S., Zhang, H., Estes, A., Brune, C. W., Bradfield, J. P., Imielinski, M., Frackelton, E. C., Reichert, J., Crawford, E. L., Munson, J., Sleiman, P. M., Chiavacci, R., Annaiah, K., Thomas, K., Hou, C., Glaberson, W., Flory, J., Otieno, F., Garris, M., Soorya, L., Klei, L., Piven, J., Meyer, K. J., Anagnostou, E., Sakurai, T., Game, R. M., Rudd, D. S., Zurawiecki, D., McDougle, C. J., Davis, L. K., Miller, J., Posey, D. J., Michaels, S., Kolevzon, A., Silverman, J. M., Bernier, R., Levy, S. E., Schultz, R. T., Dawson, G., Owley, T., McMahon, W. M., Wassink, T. H., Sweeney, J. A., Nurnberger, J. I., Coon, H., Sutcliffe, J. S., Minshew, N. J., Grant, S. F., Bucan, M., Cook, E. H., Buxbaum, J. D., Devlin, B., Schellenberg, G. D., and Hakonarson, H. (2009) Autism Genome-Wide Copy Number Variation Reveals Ubiquitin and Neuronal Genes. Nature. 459, 569-573.

Posted On

2011-04-12