Q9UBF9 (MYOTI_HUMAN) Reviewed, UniProtKB/Swiss-Prot

Names and origin

Protein names

Recommended name:
Myotilin

Alternative name(s):
57 kDa cytoskeletal protein
Myofibrillar titin-like Ig domains protein
Titin immunoglobulin domain protein

Gene names

Name:	MYOT
Synonyms:	TTID

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	498 AA.
Sequence status	Complete.
Protein existence	Evidence at protein level

General annotation (Comments)

Function	Component of a complex of multiple actin cross-linking proteins. Involved in the control of myofibril assembly and stability at the Z lines in muscle cells. Ref.7
Subunit structure	Homodimer. Interacts with ACTA1, ACTN1, FLNA, FLNB, FLNC and MYOZ2. Interacts with the C-terminal region of MYOZ1. Ref.2 Ref.6 Ref.7 Ref.8 Ref.11
Subcellular location	Cell membrane › sarcolemma. Cytoplasm › cytoskeleton. Cytoplasm › myofibril › sarcomere › Z line. Note: Sarcomeric, also localized to the sarcolemma. Colocalizes with MYOZ1 at the Z-lines in skeletal muscle. Ref.2 Ref.8
Tissue specificity	Expressed in skeletal muscle (at protein level). Expressed in skeletal muscle, heart, bone marrow and thyroid gland. Ref.1 Ref.2
Involvement in disease	Limb-girdle muscular dystrophy 1A (LGMD1A) [MIM:159000]: An autosomal dominant degenerative myopathy with onset within a mean age of 28 years. Characterized by progressive skeletal muscle weakness of the hip and shoulder girdles, later progressing to include distal weakness, as well as a distinctive dysarthric pattern of speech. Affected muscle exhibits disorganization and streaming of the Z-line. Note: The disease is caused by mutations affecting the gene represented in this entry. Ref.11 Ref.12 Myopathy, myofibrillar, 3 (MFM3) [MIM:609200]: A neuromuscular disorder characterized by progressive skeletal muscle weakness greater distally than proximally, tight heel cords, hyporeflexia, cardiomyopathy and peripheral neuropathy in some patients. Affected muscle exhibits disorganization and streaming of the Z-line, presence of large hyaline structures, excessive accumulation of myotilin and other ectopically expressed proteins and prominent congophilic deposits. Note: The disease is caused by mutations affecting the gene represented in this entry. Ref.13 Spheroid body myopathy (SBM) [MIM:182920]: Autosomal dominant form of myofibrillar myopathy (MFM), characterized by slowly progressing proximal muscle weakness and dysarthric nasal speech. There is no evidence of cardiomyopathy. Muscle biopsy shows spheroid bodies within the type I muscle fibers. Note: The disease is caused by mutations affecting the gene represented in this entry. Ref.15
Sequence similarities	Belongs to the myotilin/palladin family. Contains 2 Ig-like C2-type (immunoglobulin-like) domains.

Ontologies

Keywords
Cellular component	Cell membrane Cytoplasm Cytoskeleton Membrane
Coding sequence diversity	Alternative splicing Polymorphism
Disease	Disease mutation Limb-girdle muscular dystrophy Myofibrillar myopathy
Domain	Immunoglobulin domain Repeat
Ligand	Actin-binding
Molecular function	Muscle protein
Technical term	3D-structure Complete proteome Reference proteome
Gene Ontology (GO)
Biological_process	muscle contraction Traceable author statement Ref.11. Source: ProtInc
Cellular_component	Z disc Inferred from electronic annotation. Source: UniProtKB-SubCell actin cytoskeleton Traceable author statement Ref.2. Source: ProtInc sarcolemma Inferred from electronic annotation. Source: UniProtKB-SubCell
Molecular_function	structural constituent of muscle Traceable author statement Ref.11. Source: ProtInc
Complete GO annotation...

Binary interactions

With	Entry	#Exp.	IntAct	Notes
FLNC	Q14315	6	EBI-296701,EBI-489954

Alternative products

This entry describes 2 isoforms produced by alternative splicing. [Align] [Select]

Isoform 1 (identifier: Q9UBF9-1)

This isoform has been chosen as the 'canonical' sequence. All positional information in this entry refers to it. This is also the sequence that appears in the downloadable versions of the entry.

Isoform 2 (identifier: Q9UBF9-2)

The sequence of this isoform differs from the canonical sequence as follows:
     1-184: Missing.

Note: No experimental confirmation available.

Sequence annotation (Features)

Feature key

Position(s)

Length

Description

Graphical view

Feature identifier

Molecule processing

Chain

1 – 498

498

Myotilin

PRO_0000072687

Regions

Domain

250 – 335

86

Ig-like C2-type 1

Domain

349 – 441

93

Ig-like C2-type 2

Region

79 – 150

72

Necessary for interaction with ACTN1

Region

215 – 498

284

Necessary for interaction with ACTA1

Region

215 – 493

279

Necessary for interaction with FLNC

Natural variations

Alternative sequence

1 – 184

184

Missing in isoform 2.

VSP_041450

Natural variant

33

1

S → I in a colorectal cancer sample; somatic mutation. Ref.16

VAR_035520

Natural variant

39

1

S → F in SBM. Ref.15

VAR_029532

Natural variant

50

1

Q → R.
Corresponds to variant rs34717730 [ dbSNP | Ensembl ].

VAR_049914

Natural variant

55

1

S → F in LGMD1A and MFM3. Ref.12 Ref.13

VAR_021569

Natural variant

57

1

T → I in LGMD1A; does not abolish interaction with ACTN1. Ref.11
Corresponds to variant rs28937597 [ dbSNP | Ensembl ].

VAR_021570

Natural variant

60

1

S → C in MFM3. Ref.13

VAR_021571

Natural variant

60

1

S → F in MFM3. Ref.13

VAR_021572

Natural variant

74

1

K → Q. Ref.1 Ref.2 Ref.5
Corresponds to variant rs41431944 [ dbSNP | Ensembl ].

VAR_029533

Natural variant

95

1

S → I in MFM3. Ref.13

VAR_021573

Secondary structure

1

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

498

Helix Strand Turn

Details...

Beta strand

249 – 251

3

Beta strand

259 – 262

4

Beta strand

267 – 272

6

Beta strand

274 – 277

4

Beta strand

280 – 285

6

Beta strand

288 – 290

3

Beta strand

294 – 296

3

Beta strand

298 – 301

4

Turn

302 – 304

3

Beta strand

305 – 312

8

Helix

315 – 317

3

Beta strand

319 – 327

9

Beta strand

330 – 341

12

Beta strand

351 – 353

3

Beta strand

358 – 361

4

Beta strand

364 – 372

9

Beta strand

379 – 384

6

Beta strand

396 – 400

5

Beta strand

405 – 413

9

Helix

415 – 417

3

Beta strand

419 – 427

9

Beta strand

430 – 441

12

Sequences

	Sequence		Length	Mass (Da)
	Isoform 1 [UniParc]. Last modified November 2, 2010. Version 2. Checksum: 7F226DD43A0C611B	FASTA	498	55,395
	10 20 30 40 50 60 MFNYERPKHF IQSQNPCGSR LQPPGPETSS FSSQTKQSSI IIQPRQCTEQ RFSASSTLSS 70 80 90 100 110 120 HITMSSSAFP ASPKQHAGSN PGQRVTTTYN QSPASFLSSI LPSQPDYNSS KIPSAMDSNY 130 140 150 160 170 180 QQSSAGQPIN AKPSQTANAK PIPRTPDHEI QGSKEALIQD LERKLKCKDT LLHNGNQRLT 190 200 210 220 230 240 YEEKMARRLL GPQNAAAVFQ AQDDSGAQDS QQHNSEHARL QVPTSQVRSR STSRGDVNDQ 250 260 270 280 290 300 DAIQEKFYPP RFIQVPENMS IDEGRFCRMD FKVSGLPAPD VSWYLNGRTV QSDDLHKMIV 310 320 330 340 350 360 SEKGLHSLIF EVVRASDAGA YACVAKNRAG EATFTVQLDV LAKEHKRAPM FIYKPQSKKV 370 380 390 400 410 420 LEGDSVKLEC QISAIPPPKL FWKRNNEMVQ FNTDRISLYQ DNTGRVTLLI KDVNKKDAGW 430 440 450 460 470 480 YTVSAVNEAG VTTCNTRLDV TARPNQTLPA PKQLRVRPTF SKYLALNGKG LNVKQAFNPE 490 GEFQRLAAQS GLYESEEL
	Isoform 2 [UniParc]. Checksum: F4B4033F166A94D2	FASTA	314	35,147
	10 20 30 40 50 60 MARRLLGPQN AAAVFQAQDD SGAQDSQQHN SEHARLQVPT SQVRSRSTSR GDVNDQDAIQ 70 80 90 100 110 120 EKFYPPRFIQ VPENMSIDEG RFCRMDFKVS GLPAPDVSWY LNGRTVQSDD LHKMIVSEKG 130 140 150 160 170 180 LHSLIFEVVR ASDAGAYACV AKNRAGEATF TVQLDVLAKE HKRAPMFIYK PQSKKVLEGD 190 200 210 220 230 240 SVKLECQISA IPPPKLFWKR NNEMVQFNTD RISLYQDNTG RVTLLIKDVN KKDAGWYTVS 250 260 270 280 290 300 AVNEAGVTTC NTRLDVTARP NQTLPAPKQL RVRPTFSKYL ALNGKGLNVK QAFNPEGEFQ 310 RLAAQSGLYE SEEL

References

	« Hide 'large scale' referencesShow 'large scale' references »
[1]	"TTID: a novel gene at 5q31 encoding a protein with titin-like features." Godley L.A., Lai F., Liu J., Zhao N., Le Beau M.M. Genomics 60:226-233(1999) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), TISSUE SPECIFICITY, VARIANT GLN-74. Tissue: Bone marrow.
[2]	"Myotilin, a novel sarcomeric protein with two Ig-like domains, is encoded by a candidate gene for limb-girdle muscular dystrophy." Salmikangas P., Mykkaenen O.M., Groenholm M., Heiska L., Kere J., Carpen O. Hum. Mol. Genet. 8:1329-1336(1999) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), SUBUNIT, INTERACTION WITH ACTN1, SUBCELLULAR LOCATION, TISSUE SPECIFICITY, VARIANT GLN-74. Tissue: Skeletal muscle.
[3]	"Complete sequencing and characterization of 21,243 full-length human cDNAs." Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R., Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H., Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S. , Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K., Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A., Sudo H., Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M., Takahashi M., Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y., Abe K., Kamihara K., Katsuta N., Sato K., Tanikawa M., Yamazaki M., Ninomiya K., Ishibashi T., Yamashita H., Murakawa K., Fujimori K., Tanai H., Kimata M., Watanabe M., Hiraoka S., Chiba Y., Ishida S., Ono Y., Takiguchi S., Watanabe S., Yosida M., Hotuta T., Kusano J., Kanehori K., Takahashi-Fujii A., Hara H., Tanase T.-O., Nomura Y., Togiya S., Komai F., Hara R., Takeuchi K., Arita M., Imose N., Musashino K., Yuuki H., Oshima A., Sasaki N., Aotsuka S., Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S., Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O., Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H., Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B., Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y., Fujimori Y., Komiyama M., Tashiro H., Tanigami A., Fujiwara T., Ono T., Yamada K., Fujii Y., Ozaki K., Hirao M., Ohmori Y., Kawabata A., Hikiji T., Kobatake N., Inagaki H., Ikema Y., Okamoto S., Okitani R., Kawakami T., Noguchi S., Itoh T., Shigeta K., Senba T., Matsumura K., Nakajima Y., Mizuno T., Morinaga M., Sasaki M., Togashi T., Oyama M., Hata H., Watanabe M., Komatsu T., Mizushima-Sugano J., Satoh T., Shirai Y., Takahashi Y., Nakagawa K., Okumura K., Nagase T., Nomura N., Kikuchi H., Masuho Y., Yamashita R., Nakai K., Yada T., Nakamura Y., Ohara O., Isogai T., Sugano S. Nat. Genet. 36:40-45(2004) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 2). Tissue: Pericardium.
[4]	"The DNA sequence and comparative analysis of human chromosome 5." Schmutz J., Martin J., Terry A., Couronne O., Grimwood J., Lowry S., Gordon L.A., Scott D., Xie G., Huang W., Hellsten U., Tran-Gyamfi M., She X., Prabhakar S., Aerts A., Altherr M., Bajorek E., Black S. , Branscomb E., Caoile C., Challacombe J.F., Chan Y.M., Denys M., Detter J.C., Escobar J., Flowers D., Fotopulos D., Glavina T., Gomez M., Gonzales E., Goodstein D., Grigoriev I., Groza M., Hammon N., Hawkins T., Haydu L., Israni S., Jett J., Kadner K., Kimball H., Kobayashi A., Lopez F., Lou Y., Martinez D., Medina C., Morgan J., Nandkeshwar R., Noonan J.P., Pitluck S., Pollard M., Predki P., Priest J., Ramirez L., Retterer J., Rodriguez A., Rogers S., Salamov A., Salazar A., Thayer N., Tice H., Tsai M., Ustaszewska A., Vo N., Wheeler J., Wu K., Yang J., Dickson M., Cheng J.-F., Eichler E.E., Olsen A., Pennacchio L.A., Rokhsar D.S., Richardson P., Lucas S.M., Myers R.M., Rubin E.M. Nature 431:268-274(2004) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
[5]	"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] (ISOFORM 1), VARIANT GLN-74. Tissue: Liver.
[6]	"Indications for a novel muscular dystrophy pathway: gamma-filamin, the muscle-specific filamin isoform, interacts with myotilin." van der Ven P.F.M., Wiesner S., Salmikangas P., Auerbach D., Himmel M., Kempa S., Hayess K., Pacholsky D., Taivainen A., Schroeder R., Carpen O., Fuerst D.O. J. Cell Biol. 151:235-248(2000) [PubMed] [Europe PMC] [Abstract] Cited for: INTERACTION WITH FLNC.
[7]	"Myotilin, the limb-girdle muscular dystrophy 1A (LGMD1A) protein, cross-links actin filaments and controls sarcomere assembly." Salmikangas P., van der Ven P.F.M., Lalowski M., Taivainen A., Zhao F., Suila H., Schroeder R., Lappalainen P., Fuerst D.O., Carpen O. Hum. Mol. Genet. 12:189-203(2003) [PubMed] [Europe PMC] [Abstract] Cited for: FUNCTION IN MYOFIBRIL ASSEMBLY AND STABILITY, SUBUNIT, INTERACTION WITH ACTA1.
[8]	"The Z-disc proteins myotilin and FATZ-1 interact with each other and are connected to the sarcolemma via muscle-specific filamins." Gontier Y., Taivainen A., Fontao L., Sonnenberg A., van der Flier A., Carpen O., Faulkner G., Borradori L. J. Cell Sci. 118:3739-3749(2005) [PubMed] [Europe PMC] [Abstract] Cited for: INTERACTION WITH FLNA; FLNB; FLNC; MYOZ1 AND MYOZ2, SUBCELLULAR LOCATION.
[9]	"Solution structure of the first immunoglobulin domain of human myotilin." Heikkinen O., Permi P., Koskela H., Carpen O., Ylaenne J., Kilpelaeinen I. J. Biomol. NMR 44:107-112(2009) [PubMed] [Europe PMC] [Abstract] Cited for: STRUCTURE BY NMR OF 249-344.
[10]	"Solution NMR structure of the Ig-like C2-type 2 domain of human myotilin. Northeast structural genomics target HR3158." Northeast structural genomics consortium (NESG) Submitted (JUL-2009) to the PDB data bank Cited for: STRUCTURE BY NMR OF 344-449.
[11]	"Myotilin is mutated in limb girdle muscular dystrophy 1A." Hauser M.A., Horrigan S.K., Salmikangas P., Torian U.M., Viles K.D., Dancel R., Tim R.W., Taivainen A., Bartoloni L., Gilchrist J.M., Stajich J.M., Gaskell P.C., Gilbert J.R., Vance J.M., Pericak-Vance M.A., Carpen O., Westbrook C.A., Speer M.C. Hum. Mol. Genet. 9:2141-2147(2000) [PubMed] [Europe PMC] [Abstract] Cited for: VARIANT LGMD1A ILE-57, INTERACTION WITH ACTN1.
[12]	"Myotilin mutation found in second pedigree with LGMD1A." Hauser M.A., Conde C.B., Kowaljow V., Zeppa G., Taratuto A.L., Torian U.M., Vance J.M., Pericak-Vance M.A., Speer M.C., Rosa A.L. Am. J. Hum. Genet. 71:1428-1432(2002) [PubMed] [Europe PMC] [Abstract] Cited for: VARIANT LGMD1A PHE-55.
[13]	"Mutations in myotilin cause myofibrillar myopathy." Selcen D., Engel A.G. Neurology 62:1363-1371(2004) [PubMed] [Europe PMC] [Abstract] Cited for: VARIANTS MFM3 PHE-55; CYS-60; PHE-60 AND ILE-95.
[14]	Erratum Selcen D., Engel A.G. Neurology 63:405-405(2004)
[15]	"A mutation in myotilin causes spheroid body myopathy." Foroud T., Pankratz N., Batchman A.P., Pauciulo M.W., Vidal R., Miravalle L., Goebel H.H., Cushman L.J., Azzarelli B., Horak H., Farlow M., Nichols W.C. Neurology 65:1936-1940(2005) [PubMed] [Europe PMC] [Abstract] Cited for: VARIANT SBM PHE-39.
[16]	"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] ILE-33.
+	Additional computationally mapped references.

Web resources

GeneReviews

Cross-references

Sequence databases

EMBL
GenBank
DDBJ

AF133820 mRNA. Translation: AAD29051.2.
AF144477 mRNA. Translation: AAD44754.1.
AK300088 mRNA. Translation: BAG61891.1.
AC106791 Genomic DNA. No translation available.
BC005376 mRNA. Translation: AAH05376.1.

IPI

IPI00009551.
IPI00914545.

RefSeq

NP_001129412.1. NM_001135940.1.
NP_006781.1. NM_006790.2.

UniGene

Hs.84665.

3D structure databases

PDBe
RCSB PDB
PDBj

Entry	Method	Resolution (Å)	Chain	Positions	PDBsum
2KDG	NMR	-	A	249-344	[»]
2KKQ	NMR	-	A	344-449	[»]

ProteinModelPortal

Q9UBF9.

SMR

Q9UBF9. Positions 249-449.

ModBase

Search...

Protein-protein interaction databases

IntAct

Q9UBF9. 7 interactions.

STRING

9606.ENSP00000239926.

PTM databases

PhosphoSite

Q9UBF9.

Polymorphism databases

DMDM

311033402.

Proteomic databases

PaxDb

Q9UBF9.

PRIDE

Q9UBF9.

Protocols and materials databases

DNASU

9499.

StructuralBiologyKnowledgebase

Search...

Genome annotation databases

Ensembl

ENST00000239926; ENSP00000239926; ENSG00000120729.
ENST00000421631; ENSP00000391185; ENSG00000120729.

GeneID

9499.

KEGG

hsa:9499.

UCSC

uc003lbv.3. human.

Organism-specific databases

CTD

9499.

GeneCards

GC05P137203.

HGNC

HGNC:12399. MYOT.

HPA

HPA037733.

MIM

159000. phenotype.
182920. phenotype.
604103. gene.
609200. phenotype.

neXtProt

NX_Q9UBF9.

Orphanet

266. Autosomal dominant limb-girdle muscular dystrophy type 1A.
98911. Myotilin-related myofibrillar myopathy without spheroid body.

PharmGKB

PA37064.

GenAtlas

Search...

Phylogenomic databases

eggNOG

NOG147321.

HOGENOM

HOG000028074.

HOVERGEN

HBG066530.

InParanoid

Q9UBF9.

OMA

DSVKLEC.

OrthoDB

EOG4NVZM2.

PhylomeDB

Q9UBF9.

Gene expression databases

ArrayExpress

Q9UBF9.

Bgee

Q9UBF9.

CleanEx

HS_MYOT.

Genevestigator

Q9UBF9.

GermOnline

ENSG00000120729. Homo sapiens.

Family and domain databases

Gene3D

2.60.40.10. 2 hits.

InterPro

IPR007110. Ig-like_dom.
IPR013783. Ig-like_fold.
IPR013098. Ig_I-set.
IPR003599. Ig_sub.
IPR003598. Ig_sub2.
[Graphical view]

Pfam

PF07679. I-set. 2 hits.
[Graphical view]

SMART

SM00409. IG. 1 hit.
SM00408. IGc2. 1 hit.
[Graphical view]

PROSITE

PS50835. IG_LIKE. 2 hits.
[Graphical view]

ProtoNet

Search...

Other

ChiTaRS

MYOT. human.

EvolutionaryTrace

Q9UBF9.

GenomeRNAi

9499.

NextBio

35590.

SOURCE

Search...

Entry information

Entry name

MYOTI_HUMAN

Accession

Primary (citable) accession number: Q9UBF9
Secondary accession number(s): A0A4R6, B4DT79

Entry history

Integrated into UniProtKB/Swiss-Prot:	March 29, 2005
Last sequence update:	November 2, 2010
Last modified:	May 1, 2013
This is version 114 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.