Phenotypic Mutation 'ares2' (pdf version)
Alleleares2
Mutation Type nonsense
Chromosome6
Coordinate85,654,972 bp (GRCm39)
Base Change C ⇒ T (forward strand)
Gene Alms1
Gene Name ALMS1, centrosome and basal body associated
Synonym(s) Alstrom syndrome 1
Chromosomal Location 85,564,513-85,679,735 bp (+) (GRCm39)
MGI Phenotype FUNCTION: [Summary is not available for the mouse gene. This summary is for the human ortholog.] This gene encodes a protein containing a large tandem-repeat domain as well as additional low complexity regions. The encoded protein functions in microtubule organization, particularly in the formation and maintanance of cilia. Mutations in this gene cause Alstrom syndrome. There is a pseudogene for this gene located adjacent in the same region of chromosome 2. Alternative splice variants have been described but their full length nature has not been determined. [provided by RefSeq, Apr 2014]
PHENOTYPE: Homozygous null mice display obesity starting after puberty, hypogonadism, hyperinsulinemia, male-specific hyperglycemia, retinal dysfunction, and late-onset hearing loss. [provided by MGI curators]
Accession Number

NCBI RefSeq: NM_145223; MGI:1934606

MappedYes 
Amino Acid Change Glutamine changed to Stop codon
Institutional SourceBeutler Lab
Gene Model predicted gene model for protein(s): [ENSMUSP00000071904] [ENSMUSP00000148796]
AlphaFold no structure available at present
SMART Domains Protein: ENSMUSP00000071904
Gene: ENSMUSG00000063810
AA Change: Q2704*

DomainStartEndE-ValueType
coiled coil region 10 39 N/A INTRINSIC
low complexity region 67 80 N/A INTRINSIC
low complexity region 98 119 N/A INTRINSIC
Blast:MYSc 127 233 1e-21 BLAST
internal_repeat_3 408 511 2.48e-7 PROSPERO
internal_repeat_2 414 804 2.09e-12 PROSPERO
internal_repeat_1 438 834 4.54e-18 PROSPERO
internal_repeat_3 652 757 2.48e-7 PROSPERO
low complexity region 903 908 N/A INTRINSIC
internal_repeat_1 916 1385 4.54e-18 PROSPERO
internal_repeat_2 1024 1390 2.09e-12 PROSPERO
low complexity region 1572 1586 N/A INTRINSIC
low complexity region 2004 2017 N/A INTRINSIC
low complexity region 2760 2773 N/A INTRINSIC
low complexity region 2950 2968 N/A INTRINSIC
low complexity region 3013 3030 N/A INTRINSIC
Pfam:ALMS_motif 3125 3247 1.8e-42 PFAM
Predicted Effect probably null
Predicted Effect probably null
Meta Mutation Damage Score 0.9755 question?
Is this an essential gene? Non Essential (E-score: 0.000) question?
Phenotypic Category Autosomal Recessive
Candidate Explorer Status loading ...
Single pedigree
Linkage Analysis Data
Penetrance  
Alleles Listed at MGI

All Mutations and Alleles(16) : Chemically induced (ENU) (3) Gene trapped(9) Spontaneous(2) Targeted(2)

Lab Alleles
AlleleSourceChrCoordTypePredicted EffectPPH Score
IGL00227:Alms1 APN 6 85654946 missense probably damaging 1.00
IGL00331:Alms1 APN 6 85618353 missense possibly damaging 0.94
IGL00658:Alms1 APN 6 85605943 missense probably damaging 1.00
IGL00835:Alms1 APN 6 85599116 missense probably damaging 1.00
IGL00930:Alms1 APN 6 85578292 missense probably damaging 0.98
IGL01446:Alms1 APN 6 85673683 missense probably damaging 1.00
IGL01448:Alms1 APN 6 85654881 missense possibly damaging 0.93
IGL01563:Alms1 APN 6 85604965 missense probably damaging 1.00
IGL01632:Alms1 APN 6 85604928 missense probably benign 0.07
IGL01651:Alms1 APN 6 85633458 missense probably benign 0.05
IGL01670:Alms1 APN 6 85655132 missense probably benign 0.00
IGL01716:Alms1 APN 6 85605076 missense probably benign 0.01
IGL01719:Alms1 APN 6 85605076 missense probably benign 0.01
IGL01720:Alms1 APN 6 85605076 missense probably benign 0.01
IGL01723:Alms1 APN 6 85605076 missense probably benign 0.01
IGL01877:Alms1 APN 6 85599393 missense possibly damaging 0.55
IGL01919:Alms1 APN 6 85604986 missense possibly damaging 0.77
IGL01976:Alms1 APN 6 85599647 missense possibly damaging 0.73
IGL02003:Alms1 APN 6 85599205 missense possibly damaging 0.54
IGL02069:Alms1 APN 6 85605805 missense probably benign 0.12
IGL02070:Alms1 APN 6 85628385 missense possibly damaging 0.74
IGL02079:Alms1 APN 6 85605616 missense probably damaging 0.98
IGL02081:Alms1 APN 6 85597285 missense possibly damaging 0.55
IGL02379:Alms1 APN 6 85606615 missense probably damaging 0.98
IGL02412:Alms1 APN 6 85605854 missense possibly damaging 0.91
IGL02606:Alms1 APN 6 85576949 missense probably benign
IGL02636:Alms1 APN 6 85605636 missense probably benign 0.28
IGL02702:Alms1 APN 6 85576831 missense probably benign 0.12
IGL02815:Alms1 APN 6 85644939 critical splice donor site probably null
IGL02926:Alms1 APN 6 85618432 missense probably damaging 1.00
IGL02945:Alms1 APN 6 85597915 missense probably damaging 0.96
IGL02959:Alms1 APN 6 85606034 nonsense probably null
IGL03124:Alms1 APN 6 85655401 missense probably benign 0.03
IGL03199:Alms1 APN 6 85599479 missense possibly damaging 0.68
IGL03209:Alms1 APN 6 85576955 splice site probably benign
IGL03247:Alms1 APN 6 85655579 missense possibly damaging 0.85
ares UTSW 6 85598257 nonsense probably null
butterball UTSW 6 85673753 missense probably damaging 0.99
earthquake UTSW 6 85605717 nonsense probably null
fatty UTSW 6 85604916 nonsense probably null
gut_check UTSW 6 85597351 nonsense probably null
portly UTSW 6 85596694 missense probably benign 0.00
replete UTSW 6 85606190 missense possibly damaging 0.87
PIT4468001:Alms1 UTSW 6 85601701 critical splice donor site probably null
R0003:Alms1 UTSW 6 85606192 missense possibly damaging 0.90
R0095:Alms1 UTSW 6 85597235 missense possibly damaging 0.90
R0110:Alms1 UTSW 6 85597351 nonsense probably null
R0114:Alms1 UTSW 6 85596785 missense probably benign 0.00
R0153:Alms1 UTSW 6 85618363 missense possibly damaging 0.94
R0217:Alms1 UTSW 6 85599912 missense probably damaging 0.99
R0328:Alms1 UTSW 6 85587796 splice site probably null
R0410:Alms1 UTSW 6 85564785 missense unknown
R0469:Alms1 UTSW 6 85597351 nonsense probably null
R0491:Alms1 UTSW 6 85679582 missense probably damaging 0.98
R0510:Alms1 UTSW 6 85597351 nonsense probably null
R0522:Alms1 UTSW 6 85598597 missense probably benign
R0525:Alms1 UTSW 6 85564742 missense unknown
R0611:Alms1 UTSW 6 85655653 missense possibly damaging 0.61
R0637:Alms1 UTSW 6 85600015 missense possibly damaging 0.85
R0718:Alms1 UTSW 6 85598803 missense probably benign 0.00
R0831:Alms1 UTSW 6 85605502 missense probably benign 0.00
R1318:Alms1 UTSW 6 85605531 missense possibly damaging 0.62
R1340:Alms1 UTSW 6 85644939 critical splice donor site probably null
R1561:Alms1 UTSW 6 85606034 nonsense probably null
R1648:Alms1 UTSW 6 85655384 missense probably damaging 0.99
R1697:Alms1 UTSW 6 85599436 missense possibly damaging 0.94
R1699:Alms1 UTSW 6 85599862 missense possibly damaging 0.46
R1715:Alms1 UTSW 6 85606034 nonsense probably null
R1723:Alms1 UTSW 6 85605735 missense probably damaging 1.00
R1734:Alms1 UTSW 6 85618532 critical splice donor site probably null
R1758:Alms1 UTSW 6 85605487 missense probably damaging 0.99
R1804:Alms1 UTSW 6 85598257 nonsense probably null
R1835:Alms1 UTSW 6 85655485 missense possibly damaging 0.94
R1836:Alms1 UTSW 6 85655485 missense possibly damaging 0.94
R2077:Alms1 UTSW 6 85599291 missense possibly damaging 0.93
R2246:Alms1 UTSW 6 85599949 missense possibly damaging 0.91
R2254:Alms1 UTSW 6 85596830 missense probably damaging 1.00
R2280:Alms1 UTSW 6 85654955 missense probably damaging 0.99
R2516:Alms1 UTSW 6 85644945 splice site probably benign
R2519:Alms1 UTSW 6 85644945 splice site probably benign
R2566:Alms1 UTSW 6 85599464 missense possibly damaging 0.84
R2850:Alms1 UTSW 6 85644945 splice site probably benign
R2850:Alms1 UTSW 6 85598281 missense probably benign 0.00
R2932:Alms1 UTSW 6 85597544 missense possibly damaging 0.89
R2944:Alms1 UTSW 6 85605373 missense probably damaging 1.00
R2980:Alms1 UTSW 6 85605817 missense probably damaging 1.00
R3084:Alms1 UTSW 6 85655122 missense probably benign
R3086:Alms1 UTSW 6 85655122 missense probably benign
R3122:Alms1 UTSW 6 85644945 splice site probably benign
R3404:Alms1 UTSW 6 85644945 splice site probably benign
R3405:Alms1 UTSW 6 85644945 splice site probably benign
R3804:Alms1 UTSW 6 85596629 missense probably damaging 1.00
R3904:Alms1 UTSW 6 85598660 missense probably benign 0.00
R4014:Alms1 UTSW 6 85655334 missense probably benign 0.41
R4056:Alms1 UTSW 6 85564785 missense unknown
R4067:Alms1 UTSW 6 85598271 missense probably damaging 1.00
R4110:Alms1 UTSW 6 85597870 missense probably benign 0.00
R4111:Alms1 UTSW 6 85597870 missense probably benign 0.00
R4112:Alms1 UTSW 6 85597870 missense probably benign 0.00
R4194:Alms1 UTSW 6 85654972 nonsense probably null
R4464:Alms1 UTSW 6 85597003 missense possibly damaging 0.66
R4539:Alms1 UTSW 6 85597460 missense possibly damaging 0.78
R4554:Alms1 UTSW 6 85601599 missense probably benign
R4696:Alms1 UTSW 6 85597504 missense probably damaging 1.00
R4825:Alms1 UTSW 6 85655227 missense probably damaging 0.99
R4921:Alms1 UTSW 6 85605528 missense probably benign 0.13
R5030:Alms1 UTSW 6 85604946 missense probably damaging 0.98
R5051:Alms1 UTSW 6 85604916 nonsense probably null
R5085:Alms1 UTSW 6 85597714 missense possibly damaging 0.55
R5141:Alms1 UTSW 6 85598414 missense probably benign 0.01
R5233:Alms1 UTSW 6 85633353 splice site probably null
R5310:Alms1 UTSW 6 85592350 missense possibly damaging 0.79
R5344:Alms1 UTSW 6 85673771 missense probably benign 0.04
R5394:Alms1 UTSW 6 85600070 missense probably benign 0.01
R5460:Alms1 UTSW 6 85673713 missense probably benign 0.08
R5558:Alms1 UTSW 6 85618311 nonsense probably null
R5650:Alms1 UTSW 6 85597253 missense probably damaging 1.00
R5667:Alms1 UTSW 6 85673753 missense probably damaging 0.99
R5671:Alms1 UTSW 6 85606190 missense possibly damaging 0.87
R5688:Alms1 UTSW 6 85576877 missense possibly damaging 0.92
R5815:Alms1 UTSW 6 85599820 missense probably damaging 0.99
R5892:Alms1 UTSW 6 85597885 missense probably damaging 0.99
R5947:Alms1 UTSW 6 85596694 missense probably benign 0.00
R6031:Alms1 UTSW 6 85599937 missense probably damaging 1.00
R6031:Alms1 UTSW 6 85599937 missense probably damaging 1.00
R6144:Alms1 UTSW 6 85600056 missense probably damaging 0.98
R6258:Alms1 UTSW 6 85605717 nonsense probably null
R6260:Alms1 UTSW 6 85605717 nonsense probably null
R6455:Alms1 UTSW 6 85673639 missense probably damaging 0.99
R6569:Alms1 UTSW 6 85618321 missense probably benign 0.07
R6637:Alms1 UTSW 6 85596716 missense possibly damaging 0.78
R6866:Alms1 UTSW 6 85598080 missense possibly damaging 0.85
R6918:Alms1 UTSW 6 85599643 missense possibly damaging 0.87
R7121:Alms1 UTSW 6 85601604 missense probably damaging 1.00
R7179:Alms1 UTSW 6 85598351 missense probably benign 0.09
R7334:Alms1 UTSW 6 85618432 missense probably damaging 0.99
R7376:Alms1 UTSW 6 85599088 missense probably benign 0.10
R7394:Alms1 UTSW 6 85599205 missense possibly damaging 0.54
R7413:Alms1 UTSW 6 85605288 missense probably benign 0.03
R7511:Alms1 UTSW 6 85586407 missense unknown
R7542:Alms1 UTSW 6 85606344 missense possibly damaging 0.62
R7562:Alms1 UTSW 6 85597394 missense probably damaging 1.00
R7575:Alms1 UTSW 6 85599141 missense possibly damaging 0.49
R7577:Alms1 UTSW 6 85592302 missense probably benign 0.09
R7618:Alms1 UTSW 6 85655399 missense probably benign 0.07
R7653:Alms1 UTSW 6 85597577 missense possibly damaging 0.47
R7672:Alms1 UTSW 6 85592333 missense probably damaging 1.00
R7807:Alms1 UTSW 6 85599958 missense possibly damaging 0.91
R7815:Alms1 UTSW 6 85592340 missense probably benign 0.42
R7849:Alms1 UTSW 6 85598479 missense possibly damaging 0.48
R7944:Alms1 UTSW 6 85618362 missense probably benign 0.03
R7954:Alms1 UTSW 6 85598144 missense probably damaging 0.98
R7971:Alms1 UTSW 6 85605661 missense probably benign
R8048:Alms1 UTSW 6 85618316 missense probably benign 0.13
R8223:Alms1 UTSW 6 85620222 nonsense probably null
R8332:Alms1 UTSW 6 85597561 missense probably benign 0.05
R8374:Alms1 UTSW 6 85585973 missense probably benign 0.41
R8470:Alms1 UTSW 6 85618357 missense probably damaging 0.99
R8755:Alms1 UTSW 6 85598556 missense probably benign 0.01
R8979:Alms1 UTSW 6 85598009 missense probably damaging 0.98
R9044:Alms1 UTSW 6 85673735 missense probably damaging 0.98
R9057:Alms1 UTSW 6 85586814 missense unknown
R9224:Alms1 UTSW 6 85598770 missense possibly damaging 0.69
R9259:Alms1 UTSW 6 85644873 missense possibly damaging 0.94
R9401:Alms1 UTSW 6 85655001 nonsense probably null
R9459:Alms1 UTSW 6 85604946 missense probably damaging 0.98
R9633:Alms1 UTSW 6 85600125 missense probably damaging 0.99
R9716:Alms1 UTSW 6 85578234 missense possibly damaging 0.84
R9730:Alms1 UTSW 6 85606420 missense probably benign 0.00
R9790:Alms1 UTSW 6 85596425 missense probably benign 0.04
R9791:Alms1 UTSW 6 85596425 missense probably benign 0.04
R9802:Alms1 UTSW 6 85606220 missense possibly damaging 0.61
X0013:Alms1 UTSW 6 85633437 missense probably damaging 1.00
X0025:Alms1 UTSW 6 85597192 missense probably damaging 0.96
Z1176:Alms1 UTSW 6 85655400 missense probably benign 0.41
Mode of Inheritance Autosomal Recessive
Local Stock
Repository
Last Updated 2021-11-16 7:56 AM by Diantha La Vine
Record Created 2016-09-30 3:13 PM
Record Posted 2018-09-13
Phenotypic Description

Figure 1. Ares2 mice exhibited fasting hyperinsulinemia. Normalized data are shown. Abbreviations: WT, wild-type; REF, homozygous reference mice; HET, heterozygous variant mice; VAR, homozygous variant mice. Mean (μ) and standard deviation (σ) are indicated.

Figure 2. Ares2 mice exhibited hyperinsulinemia 30 minutes after glucose challenge. Normalized data are shown. Abbreviations: WT, wild-type; REF, homozygous reference mice; HET, heterozygous variant mice; VAR, homozygous variant mice. Mean (μ) and standard deviation (σ) are indicated.

The ares2 phenotype was identified among N-ethyl-N-nitrosourea (ENU)-mutagenized G3 mice of the pedigree R4194, some of which showed fasting hyperinsulinemia (Figure 1) and high insulin levels 30 minutes after glucose challenge (Figure 2).

Nature of Mutation

Figure 3. Linkage mapping of the fasting hyperinsulinemia phenotype using a recessive model of inheritance. Manhattan plot shows -log10 P values (Y-axis) plotted against the chromosome positions of 50 mutations (X-axis) identified in the G1 male of pedigree R4194. Normalized phenotype data are shown for single locus linkage analysis without consideration of G2 dam identity. Horizontal pink and red lines represent thresholds of P = 0.05, and the threshold for P = 0.05 after applying Bonferroni correction, respectively.

Whole exome HiSeq sequencing of the G1 grandsire identified 50 mutations. The hyperinsulinemia phenotypes were linked to a mutation in Alms1: a C to T transition at base pair 85,677,990 (v38) on chromosome 6, or base pair 90,492 in the GenBank genomic region NC_000072 encoding Alms1. The strongest association was found with a recessive model of linkage to the normalized fasting hyperinsulinemia phenotype, wherein two variant homozygotes departed phenotypically from 24 homozygous reference mice and 23 heterozygous mice with a P value of 6.785 x 10-15 (Figure 3).  A substantial semidominant effect was observed in the assays, but the mutation is preponderantly recessive.

The mutation corresponds to residue 8,225 in the NM_145223 mRNA sequence in exon 16 of 23 total exons. 

8210 AGATACCAGGAGCGACAGAAGCAGCAGAATCCA
2699 -R--Y--Q--E--R--Q--K--Q--Q--N--P-
 

The mutated nucleotide is indicated in red. The mutation results in substitution of glutamine 2,704 to a premature stop codon (Q2704*) in the ALMS1 protein.

Illustration of Mutations in
Gene & Protein
Protein Prediction

Alms1 encodes Alström Syndrome 1 (ALMS1), which has a glutamine-rich segment (amino acids 2-80), a proline-rich segment (amino acids 90-113), a putative leucine zipper (amino acids), a large tandem repeat domain (TRD) comprised of 34 imperfect repeats of a 45-50-amino acid sequence (amino acids 440−1362), a histidine-rich region (amino acids 2582-2618), two putative nuclear localization signals, a serine-rich region, and an ALMS motif (amino acids 3124-3251) [Figure 4(1-4)]. The functional significance of the domains of ALMS1 is unknown. The ares2 mutation results in substitution of glutamine 2,704 to a premature stop codon (Q2704*) in the ALMS1 protein; residue 2,704 is within an undefined region near the C-terminus of ALMS1.

For more information about Alms1, please see the record for ares.

Putative Mechanism

ALMS1 has putative roles in cell cycle regulation, cell migration, apoptosis, extracellular matrix production, ciliary assembly and/or function, adipogenesis, cytoplasmic microtubular organization, endosomal transport, and regulation of the transport of proteins between the cytoplasm and the ciliary axoneme (4-8). ALMS1 is proposed to be involved in intracellular trafficking of one or more uncharacterized receptors to the primary cilium membrane. ALMS1 may be involved in vesicle transport from the Golgi to the cilium and/or in intraflagellar transport. When ALMS1 is present, signals from the transported receptor regulate cellular homeostasis, neurogenesis, or organ function. In the absence of ALMS1, the receptor(s) are not transported within the cilia, resulting in defective signaling. In the absence of ALMS1 there is obesity, neurosensory deficit, and organ failure.

Homozygous or compound heterozygous mutations in ALMS1 that typically result in coding of a premature stop codon and coding of a truncated protein are linked to Alström syndrome (OMIM: #203800; (2;9)]. Alström syndrome has variable symptoms including childhood obesity due to an excess accumulation of subcutaneous adipose tissue, hyperinsulinemia, acanthosis nigricans (a marker of severe insulin resistance), type 2 diabetes mellitus, hypertriglyceridemia that can lead to acute pancreatitis, hypothyroidsism, growth hormone deficiency, sensorineural hearing loss, and progressive rod-cone dystrophy leading to blindness [(10); reviewed in (11;12)].

Several Alms1 mutant mouse models (fat aussie (foz), Alms1L2131X, and Alms1-/-) have been characterized (13-15). All of the mouse models exhibited rapid weight gain due to an increase in body fat and increased eating at weaning. In addition, all of the mutant Alms1 alleles also resulted in hyperinsulinemia, increased cholesterol levels (total and HDL), moderate late-onset (after ~16 weeks) diabetes only in the male mice, steatosis of the liver, hyperplastic pancreatic islets, and hypogonadism leading to infertility in the male mice. The phenotypes of the ares2 mice indicate loss of function of ALMS1ares2.

Primers PCR Primer
ares2_pcr_F: AGAGCCTCAGCATCAACTTG
ares2_pcr_R: CTAAAGTCCCCTGTACTCTGGC

Sequencing Primer
ares2_seq_F: CCTCAGCATCAACTTGAATTTGGGAG
ares2_seq_R: GTACTCTGGCCCCTCTCTAGG
Genotyping

PCR program

1) 94°C 2:00
2) 94°C 0:30
3) 55°C 0:30
4) 72°C 1:00
5) repeat steps (2-4) 40x
6) 72°C 10:00
7) 4°C hold

The following sequence of 439 nucleotides is amplified (chromosome 6, + strand):

1   agagcctcag catcaacttg aatttgggag agcatgagaa aatacatact atcaagaatc
61  aggccagaga cccaaaaggc aaaagacaag caaatgagca aaagaaggat cagaaggtca
121 ccccagagct aacaactgag tgccccgtga gtttgaatga actctggaac agataccagg
181 agcgacagaa gcagcagaat ccatctggtg cttgtgatac gaaagagctc tccttggtgg
241 aacgacttga tcgcttggct aaactgcttc agaatcccat cacacattca ctccgggcct
301 cagaaagtgc acaggatgat agcagagggg gacatagagc cagggagtgg actgggagga
361 ggcaacaaaa acagaaaggc aagcaacaca ggaagtggag taagagccta gagaggggcc
421 agagtacagg ggactttag

Primer binding sites are underlined and the sequencing primers are highlighted; the mutated nucleotide is shown in red.

References
Science Writers Anne Murray
Illustrators Katherine Timer
AuthorsEmre Turer and Bruce Beutler