Mutagenetix > Incidental Mutation

Incidental Mutation 'P0031:Letmd1'

7670

Institutional Source

Beutler Lab

Gene Symbol

Letmd1

Ensembl Gene

ENSMUSG00000037353

Gene Name

LETM1 domain containing 1

Synonyms

HCCR1, 1110019O13Rik, HCCR-2

MMRRC Submission

038283-MU

Accession Numbers

Essential gene?

Probably non essential (E-score: 0.103) question?

Stock #

P0031 (G1)

Quality Score

Status

Validated

Chromosome

Chromosomal Location

100366904-100377045 bp(+) (GRCm39)

Type of Mutation

missense

DNA Base Change (assembly)

A to G at 100370490 bp (GRCm39)

Zygosity

Heterozygous

Amino Acid Change

Asparagine to Aspartic acid at position 62 (N62D)

Ref Sequence

ENSEMBL: ENSMUSP00000155084 (fasta)

Gene Model

predicted gene model for transcript(s): [ENSMUST00000037001] [ENSMUST00000229012] [ENSMUST00000229648] [ENSMUST00000230294]

AlphaFold

Q924L1

Predicted Effect

probably damaging
Transcript: ENSMUST00000037001
AA Change: N151D

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

SMART Domains

Protein: ENSMUSP00000037546
Gene: ENSMUSG00000037353
AA Change: N151D

Domain	Start	End	E-Value	Type
Pfam:LETM1	78	346	1.5e-72	PFAM

Predicted Effect

noncoding transcript
Transcript: ENSMUST00000180953

Predicted Effect

probably benign
Transcript: ENSMUST00000229012
AA Change: Q112R

PolyPhen 2 Score 0.271 (Sensitivity: 0.91; Specificity: 0.88)

Predicted Effect

noncoding transcript
Transcript: ENSMUST00000229372

Predicted Effect

noncoding transcript
Transcript: ENSMUST00000229457

Predicted Effect

noncoding transcript
Transcript: ENSMUST00000229596

Predicted Effect

probably damaging
Transcript: ENSMUST00000229648
AA Change: N62D

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

Predicted Effect

noncoding transcript
Transcript: ENSMUST00000230579

Predicted Effect

noncoding transcript
Transcript: ENSMUST00000230339

Predicted Effect

probably benign
Transcript: ENSMUST00000230294

Predicted Effect

noncoding transcript
Transcript: ENSMUST00000231001

Meta Mutation Damage Score

0.6221

Coding Region Coverage

1x: 80.2%
3x: 70.9%
10x: 42.6%
20x: 20.3%

Validation Efficiency

85% (81/95)

MGI Phenotype

FUNCTION: [Summary is not available for the mouse gene. This summary is for the human ortholog.] This gene encodes a mitochondrial outer membrane protein. It has a potential role in tumorigenesis, which may result from negative regulation of the p53 tumor suppressor gene. Alternatively spliced transcript variants have been noted for this gene. [provided by RefSeq, Aug 2011]

Allele List at MGI

All alleles(7) : Targeted(2) Gene trapped(5)

Other mutations in this stock

Total: 11 list
Gene	Ref	Var	Chr/Loc	Mutation	Predicted Effect	Zygosity
Dcc	A	G	18: 71,517,299 (GRCm39)		probably benign	Het
Epb41l3	T	A	17: 69,566,049 (GRCm39)	L410*	probably null	Het
Fcer1a	T	A	1: 173,052,899 (GRCm39)	K99M	probably benign	Het
Frmd4b	A	G	6: 97,330,991 (GRCm39)	F132S	probably damaging	Het
Glipr1l1	C	A	10: 111,896,292 (GRCm39)	F26L	probably benign	Het
Lyst	A	G	13: 13,838,616 (GRCm39)	E1844G	probably damaging	Het
Pcdhb4	A	G	18: 37,441,938 (GRCm39)	Y416C	probably damaging	Het
Rcn1	T	A	2: 105,219,414 (GRCm39)	K260*	probably null	Het
Tcerg1	A	G	18: 42,706,367 (GRCm39)	I1015V	probably benign	Het
Tet2	T	A	3: 133,185,963 (GRCm39)	Y1158F	possibly damaging	Het
Zmynd8	T	C	2: 165,662,618 (GRCm39)		probably benign	Het

Other mutations in Letmd1

Allele	Source	Chr	Coord	Type	Predicted Effect	PPH Score
IGL01020:Letmd1	APN	15	100,369,640 (GRCm39)	missense	probably damaging	1.00
IGL02210:Letmd1	APN	15	100,367,128 (GRCm39)	critical splice donor site	probably null
IGL02486:Letmd1	APN	15	100,372,992 (GRCm39)	missense	probably damaging	1.00
IGL02606:Letmd1	APN	15	100,372,972 (GRCm39)	missense	probably damaging	1.00
IGL03218:Letmd1	APN	15	100,367,709 (GRCm39)	missense	probably damaging	1.00
lass	UTSW	15	100,370,423 (GRCm39)	splice site	probably null
PIT4515001:Letmd1	UTSW	15	100,374,683 (GRCm39)	missense	probably damaging	1.00
R0737:Letmd1	UTSW	15	100,367,702 (GRCm39)	missense	probably damaging	1.00
R1466:Letmd1	UTSW	15	100,370,423 (GRCm39)	splice site	probably null
R1466:Letmd1	UTSW	15	100,370,423 (GRCm39)	splice site	probably null
R1584:Letmd1	UTSW	15	100,370,423 (GRCm39)	splice site	probably null
R4457:Letmd1	UTSW	15	100,373,011 (GRCm39)	missense	possibly damaging	0.54
R4641:Letmd1	UTSW	15	100,375,708 (GRCm39)	missense	probably damaging	1.00
R4724:Letmd1	UTSW	15	100,367,619 (GRCm39)	missense	probably damaging	1.00
R5463:Letmd1	UTSW	15	100,367,009 (GRCm39)	missense	probably damaging	1.00
R7407:Letmd1	UTSW	15	100,367,119 (GRCm39)	missense	probably benign	0.08
R8852:Letmd1	UTSW	15	100,373,247 (GRCm39)	missense	probably benign	0.01
Y5407:Letmd1	UTSW	15	100,373,290 (GRCm39)	critical splice donor site	probably null

Protein Function and Prediction

HCCR1 and HCCR2 are alternative splicing variants of Letmd1 [reviewed in (1)]. HCCR-2 is involved in tumorigenesis and transdifferentiation of mouse NIH/3T3 cells (2). HCCR2 is a single membrane-spanning protein with a presecretory signal peptide (2). RNAi to Letmd1 led to a suppression in the malignant features of hepatocellular carcinoma cells, an increased in the apoptotic rate, an inhibition in the expression of Bcl-2, an increase in Bax expression, and the cells were blocked in the G0/G1 stage (3).

Expression/Localization

HCCR1 and HCCR2 are expressed in normal human tissues including kidney, liver, skeletal muscle, heart, and brain (2). In addition, HCCR1 and HCCR2 are overexpressed in human leukemia and lymphoma cell lines, including chronic myelogenous leukemia cell line K-562, Burkitt's lymphoma cell line Raji, lymphoblastic leukemia cell line MOLT-4, promyelocytic leukemia cell line HL-60, and human cervical cancer cell line HeLa [(2); reviewed in (1)]. Also, HCCR2 expression was increased in fresh primary human tumor tissues, including carcinomas of the breast, kidney, ovary, and stomach (2).

Background

Transgenic mice expressing Letmd1 under the cytomegalovirus (CMV) promoter developed mammary fat pad tumors that shared characteristics with human breast adenocarcinomas (4). In these animals, HCCR2 overexpression induced the translational modification of p53. As a result, proteasomal degradation of p53 was inhibited and a subsequent downregulation in the induction of p21^WAF1, MDM2, and Bax was prevented (4).

References

1. Chung, Y. J., and Kim, J. W. (2005) Novel Oncogene HCCR: Its Diagnostic and Therapeutic Implications for Cancer. Histol Histopathol. 20, 999-1003.

2. Ko, J., Lee, Y. H., Hwang, S. Y., Lee, Y. S., Shin, S. M., Hwang, J. H., Kim, J., Kim, Y. W., Jang, S. W., Ryoo, Z. Y., Kim, I. K., Namkoong, S. E., and Kim, J. W. (2003) Identification and Differential Expression of Novel Human Cervical Cancer Oncogene HCCR-2 in Human Cancers and its Involvement in p53 Stabilization. Oncogene. 22, 4679-4689.

3. Guo, J., Yang, L., Zhang, Y., Wang, J., Wan, S., Xia, S., Yang, S., Wang, R., and Fang, D. (2011) Silencing of the HCCR2 Gene Induces Apoptosis and Suppresses the Aggressive Phenotype of Hepatocellular Carcinoma Cells in Culture. J Gastrointest Surg. 15, 1807-1813.

4. Ko, J., Shin, S. M., Oh, Y. M., Lee, Y. S., Ryoo, Z. Y., Lee, Y. H., Na, D. S., and Kim, J. W. (2004) Transgenic Mouse Model for Breast Cancer: Induction of Breast Cancer in Novel Oncogene HCCR-2 Transgenic Mice. Oncogene. 23, 1950-1953.

Posted On

2012-10-29

Science Writer

Anne Murray