Mutagenetix > Incidental Mutation

Incidental Mutation 'P0018:Nell1'

7742

Institutional Source

Beutler Lab

Gene Symbol

Nell1

Ensembl Gene

ENSMUSG00000055409

Gene Name

NEL-like 1

Synonyms

l7R6, B230343H07Rik

MMRRC Submission

038271-MU

Accession Numbers

Essential gene?

Essential (E-score: 1.000) question?

Stock #

P0018 (G1)

Quality Score

Status

Validated

Chromosome

Chromosomal Location

49625098-50513037 bp(+) (GRCm39)

Type of Mutation

missense

DNA Base Change (assembly)

A to G at 49770439 bp (GRCm39)

Zygosity

Heterozygous

Amino Acid Change

Aspartic acid to Glycine at position 166 (D166G)

Ref Sequence

ENSEMBL: ENSMUSP00000103229 (fasta)

Gene Model

predicted gene model for transcript(s): [ENSMUST00000081872] [ENSMUST00000107603] [ENSMUST00000151721]

AlphaFold

Q2VWQ2

Predicted Effect

probably damaging
Transcript: ENSMUST00000081872
AA Change: D166G

PolyPhen 2 Score 1.000 (Sensitivity: 0.00; Specificity: 1.00)

SMART Domains

Protein: ENSMUSP00000080550
Gene: ENSMUSG00000055409
AA Change: D166G

Domain	Start	End	E-Value	Type
signal peptide	1	21	N/A	INTRINSIC
TSPN	29	213	8.5e-72	SMART
LamG	81	208	1.77e-14	SMART
coiled coil region	240	266	N/A	INTRINSIC
VWC	273	331	1.45e-6	SMART
VWC	335	389	1.34e0	SMART
EGF	394	433	1.06e0	SMART
EGF_CA	434	475	7.93e-9	SMART
EGF	479	516	1.1e-2	SMART
EGF	518	547	8.32e-3	SMART
EGF_CA	549	595	1.08e-10	SMART
EGF_like	596	635	1.84e-4	SMART
VWC	634	686	1.42e0	SMART
VWC	694	749	1.83e-12	SMART

Predicted Effect

probably damaging
Transcript: ENSMUST00000107603
AA Change: D166G

PolyPhen 2 Score 1.000 (Sensitivity: 0.00; Specificity: 1.00)

SMART Domains

Protein: ENSMUSP00000103229
Gene: ENSMUSG00000055409
AA Change: D166G

Domain	Start	End	E-Value	Type
signal peptide	1	21	N/A	INTRINSIC
TSPN	29	213	8.5e-72	SMART
LamG	81	208	1.77e-14	SMART
coiled coil region	240	266	N/A	INTRINSIC
VWC	273	331	1.45e-6	SMART
VWC	335	389	1.34e0	SMART
EGF	394	433	1.06e0	SMART
EGF_CA	434	475	7.93e-9	SMART
EGF	479	516	1.1e-2	SMART
EGF	518	547	8.32e-3	SMART
EGF_like	549	588	1.84e-4	SMART
VWC	587	639	1.42e0	SMART
VWC	647	702	1.83e-12	SMART

Predicted Effect

noncoding transcript
Transcript: ENSMUST00000145096

Predicted Effect

probably damaging
Transcript: ENSMUST00000151721
AA Change: D166G

PolyPhen 2 Score 0.999 (Sensitivity: 0.14; Specificity: 0.99)

SMART Domains

Protein: ENSMUSP00000114706
Gene: ENSMUSG00000055409
AA Change: D166G

Domain	Start	End	E-Value	Type
signal peptide	1	21	N/A	INTRINSIC
TSPN	29	213	8.5e-72	SMART
LamG	81	208	1.77e-14	SMART

Predicted Effect

noncoding transcript
Transcript: ENSMUST00000154410

Meta Mutation Damage Score

0.8339

Coding Region Coverage

1x: 83.8%
3x: 77.4%
10x: 57.9%
20x: 38.3%

Validation Efficiency

72% (76/106)

MGI Phenotype

FUNCTION: [Summary is not available for the mouse gene. This summary is for the human ortholog.] This gene encodes a cytoplasmic protein that contains epidermal growth factor (EGF)-like repeats. The encoded heterotrimeric protein may be involved in cell growth regulation and differentiation. A similar protein in rodents is involved in craniosynostosis. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Dec 2013]
PHENOTYPE: Homozygous mice display perinatal lethality, respiratory failure, impaired development of the intervertebral disks, vertebrae and calvarial bones, increased skull length, and abnormal curvature of the spine. [provided by MGI curators]

Allele List at MGI

All alleles(11) : Gene trapped(2) Chemically induced(9)

Other mutations in this stock

Total: 14 list
Gene	Ref	Var	Chr/Loc	Mutation	Predicted Effect	Zygosity
AAdacl4fm3	A	T	4: 144,429,767 (GRCm39)	D407E	probably benign	Het
Brip1	C	T	11: 85,999,694 (GRCm39)	V763I	possibly damaging	Het
Cspg4b	A	G	13: 113,504,040 (GRCm39)	D1723G	possibly damaging	Het
Cxxc1	C	T	18: 74,353,992 (GRCm39)	R593C	probably damaging	Het
Erbb4	T	A	1: 68,110,835 (GRCm39)	M993L	probably benign	Het
Ftsj3	C	A	11: 106,145,634 (GRCm39)	M66I	possibly damaging	Het
Galnt2	T	A	8: 125,063,350 (GRCm39)	Y357N	probably damaging	Het
Hgsnat	C	T	8: 26,458,382 (GRCm39)		probably benign	Het
Katna1	A	T	10: 7,617,223 (GRCm39)	T72S	probably damaging	Het
Nlgn1	G	T	3: 25,490,741 (GRCm39)	P329T	probably damaging	Het
Pclo	A	T	5: 14,727,735 (GRCm39)		probably benign	Het
Robo2	T	C	16: 73,843,694 (GRCm39)	I174V	possibly damaging	Het
Sufu	A	G	19: 46,463,933 (GRCm39)		probably benign	Het
Tmub1	C	A	5: 24,651,755 (GRCm39)	A55S	possibly damaging	Het

Other mutations in Nell1

Allele	Source	Chr	Coord	Type	Predicted Effect	PPH Score
IGL00327:Nell1	APN	7	49,770,421 (GRCm39)	missense	probably damaging	0.96
IGL01434:Nell1	APN	7	50,350,956 (GRCm39)	missense	probably benign	0.01
IGL01796:Nell1	APN	7	49,825,964 (GRCm39)	splice site	probably benign
IGL02048:Nell1	APN	7	49,869,355 (GRCm39)	missense	probably damaging	0.96
IGL02239:Nell1	APN	7	49,899,398 (GRCm39)	missense	probably benign	0.08
IGL02860:Nell1	APN	7	50,498,233 (GRCm39)	missense	probably damaging	0.99
IGL02958:Nell1	APN	7	49,870,085 (GRCm39)	critical splice donor site	probably null
IGL03143:Nell1	APN	7	49,929,281 (GRCm39)	nonsense	probably null
IGL03334:Nell1	APN	7	49,712,359 (GRCm39)	splice site	probably null
D6062:Nell1	UTSW	7	49,907,939 (GRCm39)	missense	probably benign	0.21
R0004:Nell1	UTSW	7	50,210,507 (GRCm39)	splice site	probably benign
R0029:Nell1	UTSW	7	49,770,463 (GRCm39)	splice site	probably benign
R0029:Nell1	UTSW	7	49,770,463 (GRCm39)	splice site	probably benign
R0468:Nell1	UTSW	7	49,878,594 (GRCm39)	missense	probably damaging	0.97
R0483:Nell1	UTSW	7	49,879,928 (GRCm39)	missense	probably benign	0.07
R0732:Nell1	UTSW	7	50,506,135 (GRCm39)	missense	probably damaging	1.00
R0945:Nell1	UTSW	7	49,869,333 (GRCm39)	missense	probably benign	0.07
R1022:Nell1	UTSW	7	49,770,411 (GRCm39)	missense	probably damaging	1.00
R1024:Nell1	UTSW	7	49,770,411 (GRCm39)	missense	probably damaging	1.00
R1075:Nell1	UTSW	7	50,503,588 (GRCm39)	missense	probably damaging	0.98
R1291:Nell1	UTSW	7	49,879,998 (GRCm39)	missense	probably benign	0.00
R1404:Nell1	UTSW	7	50,503,621 (GRCm39)	missense	possibly damaging	0.91
R1404:Nell1	UTSW	7	50,503,621 (GRCm39)	missense	possibly damaging	0.91
R1634:Nell1	UTSW	7	50,498,306 (GRCm39)	missense	possibly damaging	0.82
R1928:Nell1	UTSW	7	50,350,943 (GRCm39)	missense	possibly damaging	0.51
R2060:Nell1	UTSW	7	50,210,578 (GRCm39)	missense	possibly damaging	0.58
R2261:Nell1	UTSW	7	50,210,569 (GRCm39)	missense	possibly damaging	0.95
R2262:Nell1	UTSW	7	50,210,569 (GRCm39)	missense	possibly damaging	0.95
R2263:Nell1	UTSW	7	50,210,569 (GRCm39)	missense	possibly damaging	0.95
R2448:Nell1	UTSW	7	50,506,135 (GRCm39)	missense	probably damaging	1.00
R2869:Nell1	UTSW	7	49,899,405 (GRCm39)	intron	probably benign
R2870:Nell1	UTSW	7	49,899,405 (GRCm39)	intron	probably benign
R2871:Nell1	UTSW	7	49,899,405 (GRCm39)	intron	probably benign
R3498:Nell1	UTSW	7	49,907,927 (GRCm39)	missense	possibly damaging	0.55
R4044:Nell1	UTSW	7	49,869,367 (GRCm39)	missense	probably damaging	1.00
R4623:Nell1	UTSW	7	49,770,310 (GRCm39)	missense	possibly damaging	0.84
R4732:Nell1	UTSW	7	50,505,965 (GRCm39)	missense	probably damaging	1.00
R4733:Nell1	UTSW	7	50,505,965 (GRCm39)	missense	probably damaging	1.00
R4941:Nell1	UTSW	7	49,712,386 (GRCm39)	missense	probably benign	0.10
R4942:Nell1	UTSW	7	49,770,397 (GRCm39)	missense	possibly damaging	0.84
R5233:Nell1	UTSW	7	49,826,062 (GRCm39)	missense	probably damaging	0.99
R5590:Nell1	UTSW	7	49,929,359 (GRCm39)	missense	probably damaging	1.00
R5673:Nell1	UTSW	7	49,878,594 (GRCm39)	missense	probably damaging	0.99
R5741:Nell1	UTSW	7	50,210,638 (GRCm39)	splice site	probably null
R6345:Nell1	UTSW	7	49,625,171 (GRCm39)	missense	possibly damaging	0.91
R6916:Nell1	UTSW	7	50,350,927 (GRCm39)	missense	probably benign	0.00
R7051:Nell1	UTSW	7	50,098,592 (GRCm39)	missense	unknown
R7302:Nell1	UTSW	7	50,506,017 (GRCm39)	missense	probably benign
R7339:Nell1	UTSW	7	49,929,297 (GRCm39)	missense	probably benign	0.01
R7831:Nell1	UTSW	7	49,632,548 (GRCm39)	missense	possibly damaging	0.85
R7913:Nell1	UTSW	7	49,929,270 (GRCm39)	missense	possibly damaging	0.93
R8094:Nell1	UTSW	7	49,770,335 (GRCm39)	missense	probably benign	0.02
R8191:Nell1	UTSW	7	50,098,622 (GRCm39)	missense	unknown
R8207:Nell1	UTSW	7	49,869,760 (GRCm39)	splice site	probably null
R8292:Nell1	UTSW	7	49,907,995 (GRCm39)	missense	probably damaging	1.00
R8340:Nell1	UTSW	7	49,870,021 (GRCm39)	missense	probably damaging	0.98
R8673:Nell1	UTSW	7	49,869,343 (GRCm39)	missense	probably damaging	1.00
R8821:Nell1	UTSW	7	50,476,097 (GRCm39)	missense	probably damaging	0.98
R8987:Nell1	UTSW	7	50,498,399 (GRCm39)	missense	probably damaging	1.00
R8988:Nell1	UTSW	7	50,210,543 (GRCm39)	missense	unknown
R9095:Nell1	UTSW	7	50,506,150 (GRCm39)	missense	possibly damaging	0.92
R9300:Nell1	UTSW	7	49,712,368 (GRCm39)	missense	probably benign
R9370:Nell1	UTSW	7	49,770,292 (GRCm39)	missense	probably damaging	1.00
R9422:Nell1	UTSW	7	49,712,387 (GRCm39)	nonsense	probably null
R9428:Nell1	UTSW	7	50,503,683 (GRCm39)	missense	probably damaging	1.00
R9445:Nell1	UTSW	7	49,632,474 (GRCm39)	missense	possibly damaging	0.78
Z1176:Nell1	UTSW	7	50,210,630 (GRCm39)	missense	unknown

Nature of Mutation

Multiple transcripts of the Nell1 gene are displayed on Ensembl and Vega.

Protein Function and Prediction

The Nell1 gene encodes an 810 amino acid secreted protein involved in the control of cell growth and differentiation. NELL1 may form a homotrimer and bind to protein kinase C beta (PKCbeta; see the record for Untied). The protein contains six epidermal growth factor (EGF)-like repeats, one TSP N-terminal domain at residues 81-230 and five VWFC (von Willebrand factor type C) domains (Uniprot Q2VWQ2). Loss of Nell1 expression results in the downregulation of several genes that encode extracellular matrix proteins such as collagens, thrombospondins, tenascins and matrilins; these proteins are essential for cell adhesion and communication as well as tissue strength and flexibility (2). Characterization of a mouse model with reduction in Nell1 expression indicates that Nell1 is involved in intramembranous and endochondral ossification during early mammalian development (2).

Expression/Localization

NELL1 is expressed primarily in human adult and fetal brain and kidney tissues (3). In the adult mouse, Nell1 is expressed primarily in the brain (2). At sites of premature suture fusion in craniosynostosis, a congenital craniofacial deformity, NELL1 is localized primarily to the mesenchymal cells and osteoblastic cells at the osteogenic front, along the parasutural bone margins, and within the condensing mesenchymal cells of newly formed bone in sutural sites (4). NELL1 is preferentially expressed in cranial intramembranous bone and neural tissue, which are both of neural crest cell origin.

Background

Nell1^{l7R6-6R/l7R6-6R}; MGI:3626314

Not Specified

This is an ENU-induced point mutation that converts a cysteine to a premature stop codon; the Nell1 transcripts are reduced (2). Homozygous mice display perinatal lethality, respiratory failure, impaired development of the intervertebral disks, vertebrae and calvarial bones, increased skull length, and abnormal curvature of the spine (2). These mice display considerable reduction in the amount of extracellular material surrounding cells in the developing vertebral bone and intervertebral discs, compared with the wild-type controls (2). In addition, histology data suggested lesser degree of bone and cartilage development in mutant animals (2).

References

1. Zhang, X., Carpenter, D., Bokui, N., Soo, C., Miao, S., Truong, T., Wu, B., Chen, I., Vastardis, H., Tanizawa, K., Kuroda, S., and Ting, K. (2003) Overexpression of Nell-1, a Craniosynostosis-Associated Gene, Induces Apoptosis in Osteoblasts during Craniofacial Development. J Bone Miner Res. 18, 2126-2134.

2. Desai, J., Shannon, M. E., Johnson, M. D., Ruff, D. W., Hughes, L. A., Kerley, M. K., Carpenter, D. A., Johnson, D. K., Rinchik, E. M., and Culiat, C. T. (2006) Nell1-Deficient Mice have Reduced Expression of Extracellular Matrix Proteins Causing Cranial and Vertebral Defects. Hum Mol Genet. 15, 1329-1341.

3. Watanabe, T. K., Katagiri, T., Suzuki, M., Shimizu, F., Fujiwara, T., Kanemoto, N., Nakamura, Y., Hirai, Y., Maekawa, H., and Takahashi, E. (1996) Cloning and Characterization of Two Novel Human cDNAs (NELL1 and NELL2) Encoding Proteins with Six EGF-Like Repeats. Genomics. 38, 273-276.

4. Ting, K., Vastardis, H., Mulliken, J. B., Soo, C., Tieu, A., Do, H., Kwong, E., Bertolami, C. N., Kawamoto, H., Kuroda, S., and Longaker, M. T. (1999) Human NELL-1 Expressed in Unilateral Coronal Synostosis. J Bone Miner Res. 14, 80-89.

Posted On

2012-10-29

Science Writer

Anne Murray