P02489 (CRYAA_HUMAN) Reviewed, UniProtKB/Swiss-Prot

Names and origin

Protein names

Recommended name:
Alpha-crystallin A chain

Alternative name(s):
Heat shock protein beta-4
Short name=HspB4

Cleaved into the following chain:

1. Alpha-crystallin A chain, short form

Gene names

Name:	CRYAA
Synonyms:	CRYA1, HSPB4

Organism

Homo sapiens (Human) [Reference proteome]

Taxonomic identifier

9606 [NCBI]

Taxonomic lineage

cellular organisms › Eukaryota › Opisthokonta › Metazoa › Eumetazoa › Bilateria › Deuterostomia › Chordata › Craniata › Vertebrata › Gnathostomata › Teleostomi › Euteleostomi › Sarcopterygii › Tetrapoda › Amniota › Mammalia › Theria › Eutheria › Euarchontoglires › Primates › Haplorrhini › Simiiformes › Catarrhini › Hominoidea › Hominidae › Homininae › Homo

Protein attributes

Sequence length	173 AA.
Sequence status	Complete.
Sequence processing	The displayed sequence is further processed into a mature form.
Protein existence	Evidence at protein level

General annotation (Comments)

Function	May contribute to the transparency and refractive index of the lens. Has chaperone-like activity, preventing aggregation of various proteins under a wide range of stress conditions. Ref.20
Subunit structure	Heteropolymer composed of three CRYAA and one CRYAB subunits. Inter-subunit bridging via zinc ions enhances stability, which is crucial as there is no protein turn over in the lens. Ref.19 Ref.21
Subcellular location	Cytoplasm. Nucleus. Note: Translocates to the nucleus during heat shock and resides in sub-nuclear structures known as SC35 speckles or nuclear splicing speckles. Ref.18
Post-translational modification	O-glycosylated; contains N-acetylglucosamine side chains. Ref.11 Deamidation of Asn-101 in lens occurs mostly during the first 30 years of age, followed by a small additional amount of deamidation (approximately 5%) during the next approximately 38 years, resulting in a maximum of approximately 50% deamidation during the lifetime of the individual. Phosphorylation on Ser-122 seems to be developmentally regulated. Absent in the first months of life, it appears during the first 12 years of human lifetime. The relative amount of phosphorylated form versus unphosphorylated form does not change over the lifetime of the individual. Ref.12 Ref.13 Ref.15 Ref.16 Acetylation at Lys-70 seems to increase chaperone activity.
Involvement in disease	Cataract autosomal dominant (ADC) [MIM:604219]: An opacification of the crystalline lens of the eye that frequently results in visual impairment or blindness. Opacities vary in morphology, are often confined to a portion of the lens, and may be static or progressive. In general, the more posteriorly located and dense an opacity, the greater the impact on visual function. Note: The disease is caused by mutations affecting the gene represented in this entry. Ref.22 Ref.23 Ref.24 Ref.27
Sequence similarities	Belongs to the small heat shock protein (HSP20) family.
Mass spectrometry	Molecular mass is 19950 Da from positions 1 - 173. Determined by ESI. Ref.12 Molecular mass is 19863 Da from positions 1 - 172. Determined by ESI. Ref.12 Molecular mass is 20029 Da from positions 1 - 173. Determined by ESI. With 1 phosphate group. Ref.12 Molecular mass is 19951 Da from positions 1 - 173. Determined by ESI. Ref.15 Molecular mass is 19864 Da from positions 1 - 172. Determined by ESI. Ref.15 Molecular mass is 19947 Da from positions 1 - 173. Determined by ESI. Ref.16 Molecular mass is 19851 Da from positions 1 - 172. Determined by ESI. Ref.16

Ontologies

Keywords
Biological process	Sensory transduction Vision
Cellular component	Cytoplasm Nucleus
Coding sequence diversity	Polymorphism
Disease	Cataract Disease mutation
Ligand	Metal-binding Zinc
Molecular function	Chaperone Eye lens protein
PTM	Acetylation Disulfide bond Glycoprotein Oxidation Phosphoprotein
Technical term	Complete proteome Direct protein sequencing Reference proteome
Gene Ontology (GO)
Biological_process	M phase specific microtubule process Inferred from electronic annotation. Source: Compara actin filament organization Inferred from electronic annotation. Source: Compara apoptotic process involved in morphogenesis Inferred from electronic annotation. Source: Compara embryonic camera-type eye morphogenesis Inferred from electronic annotation. Source: Compara lens fiber cell morphogenesis Inferred from electronic annotation. Source: Compara mitochondrion organization Inferred from electronic annotation. Source: Compara negative regulation of apoptotic process Inferred from mutant phenotype Ref.24. Source: UniProtKB negative regulation of cysteine-type endopeptidase activity involved in apoptotic process Inferred from electronic annotation. Source: Compara negative regulation of gene expression Inferred from electronic annotation. Source: Compara negative regulation of intracellular transport Inferred from direct assay PubMed 14752512. Source: HGNC positive regulation of cell growth Inferred from electronic annotation. Source: Compara positive regulation of protein phosphorylation Inferred from electronic annotation. Source: Compara protein folding Inferred from electronic annotation. Source: Compara protein homooligomerization Inferred from direct assay PubMed 16303126. Source: UniProtKB response to UV-A Inferred from electronic annotation. Source: Compara response to drug Inferred from electronic annotation. Source: Compara response to glucocorticoid stimulus Inferred from electronic annotation. Source: Compara response to hydrogen peroxide Inferred from electronic annotation. Source: Compara response to hypoxia Inferred from electronic annotation. Source: Compara response to lead ion Inferred from electronic annotation. Source: Compara tubulin complex assembly Inferred from electronic annotation. Source: Compara visual perception Inferred from mutant phenotype Ref.24PubMed 18587492Ref.22. Source: UniProtKB
Cellular_component	cytoplasm Inferred from direct assay Ref.18. Source: UniProtKB nucleus Inferred from direct assay Ref.18. Source: UniProtKB
Molecular_function	metal ion binding Inferred from electronic annotation. Source: UniProtKB-KW structural constituent of eye lens Inferred from electronic annotation. Source: UniProtKB-KW unfolded protein binding Inferred from mutant phenotype Ref.27. Source: UniProtKB
Complete GO annotation...

Sequence annotation (Features)

	Feature key	Position(s)	Length	Description	Graphical view	Feature identifier
Molecule processing
	Chain	1 – 173	173	Alpha-crystallin A chain		PRO_0000125865
	Chain	1 – 172	172	Alpha-crystallin A chain, short form		PRO_0000226639
	Propeptide	173	1	Removed in short form		PRO_0000226640
Sites
	Metal binding	79	1	Zinc
	Metal binding	107	1	Zinc
	Metal binding	115	1	Zinc
	Site	18	1	Susceptible to oxidation
	Site	34	1	Susceptible to oxidation
	Site	138	1	Susceptible to oxidation
Amino acid modifications
	Modified residue	1	1	N-acetylmethionine
	Modified residue	70	1	N6-acetyllysine Ref.15 Ref.20
	Modified residue	99	1	N6-acetyllysine Ref.20
	Modified residue	101	1	Deamidated asparagine; partial Ref.12 Ref.14 Ref.15
	Modified residue	122	1	Phosphoserine Ref.12 Ref.13
	Glycosylation	162	1	O-linked (GlcNAc) By similarity
	Disulfide bond	131 ↔ 142		Ref.12
Natural variations
	Natural variant	21	1	R → L in congenital cataract; associated with macular hypoplasia and a generally hypopigmented fundus. Ref.25		VAR_046892
	Natural variant	49	1	R → C in ADC; nuclear cataract. Ref.24		VAR_038375
	Natural variant	105	1	D → H in a breast cancer sample; somatic mutation. Ref.26		VAR_036564
	Natural variant	116	1	R → C in ADC; zonular central nuclear cataract; reduced chaperone-like activity and increased membrane-binding capacity. Ref.22 Ref.23		VAR_003819
	Natural variant	116	1	R → H in ADC; reverse phase-high-performance liquid chromatography suggests an increase hydrophobicity of the mutant protein; loss of chaperone activity of the mutant is seen in DL-dithiothreitol-induced insulin aggregation assay; fast protein liquid chromatography purification shows that the mutant protein has increased binding affinity to lysozyme. Ref.27		VAR_046893
Experimental info
	Sequence conflict	45	1	S → T in AAA52105. Ref.9
	Sequence conflict	153 – 155	3	THA → HT Ref.2

Sequences

	Sequence		Length	Mass (Da)
	P02489 [UniParc]. Last modified October 1, 1996. Version 2. Checksum: 81804A8439837D50	FASTA	173	19,909
	10 20 30 40 50 60 MDVTIQHPWF KRTLGPFYPS RLFDQFFGEG LFEYDLLPFL SSTISPYYRQ SLFRTVLDSG 70 80 90 100 110 120 ISEVRSDRDK FVIFLDVKHF SPEDLTVKVQ DDFVEIHGKH NERQDDHGYI SREFHRRYRL 130 140 150 160 170 PSNVDQSALS CSLSADGMLT FCGPKIQTGL DATHAERAIP VSREEKPTSA PSS

References

	« Hide 'large scale' referencesShow 'large scale' references »
[1]	"The amino acid sequence of the A chain of human alpha-crystallin." de Jong W.W., Terwindt E.C., Bloemendal H. FEBS Lett. 58:310-313(1975) [PubMed] [Europe PMC] [Abstract] Cited for: PRELIMINARY PROTEIN SEQUENCE.
[2]	"A reassessment of mammalian alpha A-crystallin sequences using DNA sequencing: implications for anthropoid affinities of tarsier." Jaworski C.J. J. Mol. Evol. 41:901-908(1995) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA]. Tissue: Lens.
[3]	"Cloning, expression, and chaperone-like activity of human alphaA-crystallin." Andley U.P., Mathur S., Griest T.A., Petrash J.M. J. Biol. Chem. 271:31973-31980(1996) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA]. Tissue: Lens.
[4]	"Cloning of human full open reading frames in Gateway(TM) system entry vector (pDONR201)." Ebert L., Schick M., Neubert P., Schatten R., Henze S., Korn B. Submitted (MAY-2004) to the EMBL/GenBank/DDBJ databases Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
[5]	"The DNA sequence of human chromosome 21." Hattori M., Fujiyama A., Taylor T.D., Watanabe H., Yada T., Park H.-S., Toyoda A., Ishii K., Totoki Y., Choi D.-K., Groner Y., Soeda E., Ohki M., Takagi T., Sakaki Y., Taudien S., Blechschmidt K., Polley A. , Menzel U., Delabar J., Kumpf K., Lehmann R., Patterson D., Reichwald K., Rump A., Schillhabel M., Schudy A., Zimmermann W., Rosenthal A., Kudoh J., Shibuya K., Kawasaki K., Asakawa S., Shintani A., Sasaki T., Nagamine K., Mitsuyama S., Antonarakis S.E., Minoshima S., Shimizu N., Nordsiek G., Hornischer K., Brandt P., Scharfe M., Schoen O., Desario A., Reichelt J., Kauer G., Bloecker H., Ramser J., Beck A., Klages S., Hennig S., Riesselmann L., Dagand E., Wehrmeyer S., Borzym K., Gardiner K., Nizetic D., Francis F., Lehrach H., Reinhardt R., Yaspo M.-L. Nature 405:311-319(2000) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
[6]	Mural R.J., Istrail S., Sutton G., Florea L., Halpern A.L., Mobarry C.M., Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R., Flanigan M.J., Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V., Hannenhalli S., Turner R. , Yooseph S., Lu F., Nusskern D.R., Shue B.C., Zheng X.H., Zhong F., Delcher A.L., Huson D.H., Kravitz S.A., Mouchard L., Reinert K., Remington K.A., Clark A.G., Waterman M.S., Eichler E.E., Adams M.D., Hunkapiller M.W., Myers E.W., Venter J.C. Submitted (SEP-2005) to the EMBL/GenBank/DDBJ databases Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
[7]	"The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC)." The MGC Project Team Genome Res. 14:2121-2127(2004) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA]. Tissue: Colon.
[8]	"A pseudo-exon in the functional human alpha A-crystallin gene." Jaworski C.J., Piatigorsky J. Nature 337:752-754(1989) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 1-104.
[9]	"Isolation and partial characterization of the human alpha A-crystallin gene." McDevitt D.S., Hawkins J.W., Jaworski C.J., Piatigorsky J. Exp. Eye Res. 43:285-291(1986) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 1-63 AND 166-173. Tissue: Spleen.
[10]	"Sequence analysis of betaA3, betaB3, and betaA4 crystallins completes the identification of the major proteins in young human lens." Lampi K.J., Ma Z., Shih M., Shearer T.R., Smith J.B., Smith D.L., David L.L. J. Biol. Chem. 272:2268-2275(1997) [PubMed] [Europe PMC] [Abstract] Cited for: PROTEIN SEQUENCE OF 13-21 AND 79-88.
[11]	"Vertebrate lens alpha-crystallins are modified by O-linked N-acetylglucosamine." Roquemore E.P., Dell A., Morris H.R., Panico M., Reason A.J., Savoy L.-A., Wistow G.J., Zigler J.S. Jr., Earles B.J., Hart G.W. J. Biol. Chem. 267:555-563(1992) [PubMed] [Europe PMC] [Abstract] Cited for: STRUCTURE OF CARBOHYDRATE.
[12]	"Post-translational modifications of water-soluble human lens crystallins from young adults." Miesbauer L.R., Zhou X., Yang Z., Yang Z., Sun Y., Smith D.L., Smith J.B. J. Biol. Chem. 269:12494-12502(1994) [PubMed] [Europe PMC] [Abstract] Cited for: PHOSPHORYLATION AT SER-122, DISULFIDE BOND, PROTEOLYTIC PROCESSING OF C-TERMINAL, DEAMIDATION AT ASN-101, MASS SPECTROMETRY.
[13]	"Differential phosphorylation of alpha-A crystallin in human lens of different age." Takemoto L.J. Exp. Eye Res. 62:499-504(1996) [PubMed] [Europe PMC] [Abstract] Cited for: PHOSPHORYLATION AT SER-122.
[14]	"Quantitation of asparagine-101 deamidation from alpha-A crystallin during aging of the human lens." Takemoto L.J. Curr. Eye Res. 17:247-250(1998) [PubMed] [Europe PMC] [Abstract] Cited for: DEAMIDATION AT ASN-101.
[15]	"In vivo acetylation identified at lysine 70 of human lens alphaA-crystallin." Lin P.P., Barry R.C., Smith D.L., Smith J.B. Protein Sci. 7:1451-1457(1998) [PubMed] [Europe PMC] [Abstract] Cited for: PROTEOLYTIC PROCESSING OF C-TERMINAL, ACETYLATION AT LYS-70, PHOSPHORYLATION, DEAMIDATION AT ASN-101, MASS SPECTROMETRY.
[16]	"The major in vivo modifications of the human water-insoluble lens crystallins are disulfide bonds, deamidation, methionine oxidation and backbone cleavage." Hanson S.R.A., Hasan A., Smith D.L., Smith J.B. Exp. Eye Res. 71:195-207(2000) [PubMed] [Europe PMC] [Abstract] Cited for: PHOSPHORYLATION, SUSCEPTIBILITY TO OXIDATION, PROTEOLYTIC PROCESSING OF C-TERMINAL, MASS SPECTROMETRY.
[17]	"Chaperone-like activity of alpha-crystallin and other small heat shock proteins." Ganea E. Curr. Protein Pept. Sci. 2:205-225(2001) [PubMed] [Europe PMC] [Abstract] Cited for: REVIEW.
[18]	"HSPB7 is a SC35 speckle resident small heat shock protein." Vos M.J., Kanon B., Kampinga H.H. Biochim. Biophys. Acta 1793:1343-1353(2009) [PubMed] [Europe PMC] [Abstract] Cited for: SUBCELLULAR LOCATION.
[19]	"Importance of eye lens alpha-crystallin heteropolymer with 3:1 alphaA to alphaB ratio: stability, aggregation, and modifications." Srinivas P., Narahari A., Petrash J.M., Swamy M.J., Reddy G.B. IUBMB Life 62:693-702(2010) [PubMed] [Europe PMC] [Abstract] Cited for: SUBUNIT.
[20]	"Acetylation of alphaA-crystallin in the human lens: effects on structure and chaperone function." Nagaraj R.H., Nahomi R.B., Shanthakumar S., Linetsky M., Padmanabha S., Pasupuleti N., Wang B., Santhoshkumar P., Panda A.K., Biswas A. Biochim. Biophys. Acta 1822:120-129(2012) [PubMed] [Europe PMC] [Abstract] Cited for: FUNCTION, ACETYLATION AT LYS-70 AND LYS-99.
[21]	"Identification of histidine residues involved in Zn(2+) binding to alphaA- and alphaB-Crystallin by chemical modification and MALDI TOF mass spectrometry." Karmakar S., Das K.P. Protein J. 31:623-640(2012) [PubMed] [Europe PMC] [Abstract] Cited for: SUBUNIT, ZINC-BINDING SITES.
[22]	"Autosomal dominant congenital cataract associated with a missense mutation in the human alpha crystallin gene CRYAA." Litt M., Kramer P., la Morticella D.M., Murphey W., Lovrien E.W., Weleber R.G. Hum. Mol. Genet. 7:471-474(1998) [PubMed] [Europe PMC] [Abstract] Cited for: VARIANT ADC CYS-116.
[23]	"Structural and functional changes in the alpha A-crystallin R116C mutant in hereditary cataracts." Cobb B.A., Petrash J.M. Biochemistry 39:15791-15798(2000) [PubMed] [Europe PMC] [Abstract] Cited for: CHARACTERIZATION OF VARIANT ADC CYS-116.
[24]	"Cell death triggered by a novel mutation in the alphaA-crystallin gene underlies autosomal dominant cataract linked to chromosome 21q." Mackay D.S., Andley U.P., Shiels A. Eur. J. Hum. Genet. 11:784-793(2003) [PubMed] [Europe PMC] [Abstract] Cited for: VARIANT ADC CYS-49.
[25]	"Congenital cataract and macular hypoplasia in humans associated with a de novo mutation in CRYAA and compound heterozygous mutations in P." Graw J., Klopp N., Illig T., Preising M.N., Lorenz B. Graefes Arch. Clin. Exp. Ophthalmol. 244:912-919(2006) [PubMed] [Europe PMC] [Abstract] Cited for: VARIANT CONGENITAL CATARACT LEU-21.
[26]	"The consensus coding sequences of human breast and colorectal cancers." Sjoeblom T., Jones S., Wood L.D., Parsons D.W., Lin J., Barber T.D., Mandelker D., Leary R.J., Ptak J., Silliman N., Szabo S., Buckhaults P., Farrell C., Meeh P., Markowitz S.D., Willis J., Dawson D., Willson J.K.V. , Gazdar A.F., Hartigan J., Wu L., Liu C., Parmigiani G., Park B.H., Bachman K.E., Papadopoulos N., Vogelstein B., Kinzler K.W., Velculescu V.E. Science 314:268-274(2006) [PubMed] [Europe PMC] [Abstract] Cited for: VARIANT [LARGE SCALE ANALYSIS] HIS-105.
[27]	"A novel mutation in AlphaA-crystallin (CRYAA) caused autosomal dominant congenital cataract in a large Chinese family." Gu F., Luo W., Li X., Wang Z., Lu S., Zhang M., Zhao B., Zhu S., Feng S., Yan Y.-B., Huang S., Ma X. Hum. Mutat. 29:769-769(2008) [PubMed] [Europe PMC] [Abstract] Cited for: VARIANT ADC HIS-116, CHARACTERIZATION OF VARIANT ADC HIS-116.
+	Additional computationally mapped references.

Cross-references

Sequence databases
EMBL GenBank DDBJ	U05569 mRNA. Translation: AAA97523.1. U66584 mRNA. Translation: AAC50900.1. X14789 mRNA. Translation: CAA32891.1. CR407691 mRNA. Translation: CAG28619.1. AP001631 Genomic DNA. No translation available. AP001748 Genomic DNA. Translation: BAA95535.1. CH471079 Genomic DNA. Translation: EAX09497.1. CH471079 Genomic DNA. Translation: EAX09498.1. BC069528 mRNA. Translation: AAH69528.1. BC113598 mRNA. Translation: AAI13599.1. M35628 Genomic DNA. Translation: AAA52106.1. M35629 Genomic DNA. Translation: AAA52105.1.
IPI	IPI00021062.
PIR	CYHUAA. S03344.
RefSeq	NP_000385.1. NM_000394.2.
UniGene	Hs.184085.
3D structure databases
DisProt	DP00444.
ProteinModelPortal	P02489.
ModBase	Search...
Protein-protein interaction databases
DIP	DIP-41265N.
MINT	MINT-220977.
STRING	9606.ENSP00000291554.
PTM databases
GlycoSuiteDB	P02489.
PhosphoSite	P02489.
Polymorphism databases
DMDM	1706112.
2D gel databases
SWISS-2DPAGE	P02489.
Proteomic databases
PaxDb	P02489.
PeptideAtlas	P02489.
PRIDE	P02489.
Protocols and materials databases
DNASU	1409.
StructuralBiologyKnowledgebase	Search...
Genome annotation databases
Ensembl	ENST00000291554; ENSP00000291554; ENSG00000160202.
GeneID	1409.
KEGG	hsa:1409.
UCSC	uc002zdd.1. human.
Organism-specific databases
CTD	1409.
GeneCards	GC21P044589.
HGNC	HGNC:2388. CRYAA.
MIM	123580. gene+phenotype. 604219. phenotype.
neXtProt	NX_P02489.
Orphanet	1377. Cataract-microcornea syndrome. 98991. Nuclear cataract. 98995. Zonular cataract.
PharmGKB	PA26906.
GenAtlas	Search...
Phylogenomic databases
eggNOG	NOG278874.
HOGENOM	HOG000233954.
HOVERGEN	HBG054766.
InParanoid	P02489.
KO	K09541.
OMA	GPKVQSG.
OrthoDB	EOG4F1X4B.
PhylomeDB	P02489.
Gene expression databases
ArrayExpress	P02489.
Bgee	P02489.
CleanEx	HS_CRYAA.
Genevestigator	P02489.
GermOnline	ENSG00000160202. Homo sapiens.
Family and domain databases
InterPro	IPR002068. a-crystallin/Hsp20_dom. IPR001436. Alpha-crystallin/HSP. IPR012274. Alpha-crystallin_A. IPR003090. Alpha-crystallin_N. IPR008978. HSP20-like_chaperone. [Graphical view]
PANTHER	PTHR11527:SF36. PTHR11527:SF36. 1 hit.
Pfam	PF00525. Crystallin. 1 hit. PF00011. HSP20. 1 hit. [Graphical view]
PIRSF	PIRSF036514. Sm_HSP_B1. 1 hit.
PRINTS	PR00299. ACRYSTALLIN.
SUPFAM	SSF49764. HSP20_chap. 1 hit.
PROSITE	PS01031. HSP20. 1 hit. [Graphical view]
ProtoNet	Search...
Other
GenomeRNAi	1409.
NextBio	5761.
SOURCE	Search...

Entry information

Entry name

CRYAA_HUMAN

Accession

Primary (citable) accession number: P02489
Secondary accession number(s): Q53X53

Entry history

Integrated into UniProtKB/Swiss-Prot:	July 21, 1986
Last sequence update:	October 1, 1996
Last modified:	May 1, 2013
This is version 147 of the entry and version 2 of the sequence. [Complete history]

Entry status

Reviewed (UniProtKB/Swiss-Prot)

Annotation program

Chordata Protein Annotation Program

Disclaimer

Any medical or genetic information present in this entry is provided for research, educational and informational purposes only. It is not in any way intended to be used as a substitute for professional medical advice, diagnosis, treatment or care.