Genethon marker D22S1171 is located at the 5 end of the gene (Mongroo et al., 2004). Genethon marker D22S1171 is located between exon 2 and exon 1A of the PARVB gene.
The PARVA gene is located at 11p15.3.

PARVB3/CLINT, which encodes the longer Parvin-beta protein isoform is transcribed from promoter 1 and contains two additional 5 exons (exons 1 and 2) not present in PARVB1, and comprises 14 exons in total. PARVB1 encodes the shorter Parvin-beta protein isoform, is transcribed from promoter 1A, and comprises 13 exons in total. Both promoters contain CpG islands that span the transcription start sites. PARVB3/CLINT contains 70 unique N-terminal amino acids not present in the short isoform. (See figure A).

As with PARVA, human PARVB mRNA expression is highest in heart, followed by skeletal muscle, where it localises to the sarcolemma (Yamaji et al., 2001; Matsuda et al., 2005). Both PARVB mRNA transcripts are essentially ubiquitously expressed (Korenbaum et al., 2001), but with lower expression in gastrointestinal tissues (stomach, small intestine, colon). (See figure B).

The major functional domains of Parvin-beta are two atypical calponin homology (CH) domains, termed CH1 (106 amino acids) and CH2 (107 amino acids). Each CH domain contains two actin binding sequences (ABS), although Parvin-beta has not been shown to bind actin directly (Korenbaum et al., 2001; Sepulveda and Wu, 2006). Parvin-beta physically interacts with Dysferlin and ARHGEF6 (alpha-PIX) through the CH1 domain (Matsuda et al., 2005; Rosenberger et al., 2003) and with ILK and alpha-actinin through the CH2 domain (Yamaji et al., 2001; Yamaji et al., 2004). Parvin-beta was also recently reported to directly interact with AKT (Kimura et al., 2010).

PARVB is essentially ubiquitously expressed.

Parvin-beta localises to focal adhesions but also to the nucleus, which is most likely due to NLS motifs in the N-terminal region (Mongroo et al., 2004; Johnstone et al., 2008). Parvin-beta is incorporated into focal adhesions as part of the heterotrimeric IPP complex. The ternary complex contains 1 molecule of integrin linked kinase (ILK), 1 Parvin isoform, and 1 PINCH (LIMS) isoform, (Legate et al., 2006). Binding of Parvin-alpha and Parvin-beta to the kinase domain of ILK is mutually exclusive (Zhang et al., 2004). Formation of the IPP complex also dictates total protein levels of each component, as any excess ILK, Parvin, or PINCH not incorporated into IPP is degraded in a proteasome-dependent manner (Fukuda et al., 2003).

Parvin-beta participates in focal adhesion dynamics through involvement in the IPP complex. The high expression levels in cardiac and skeletal muscle suggest important function(s) in these organs. In skeletal muscle, it binds dysferlin at the sarcolemma and thus may be involved with membrane repair (Yamaji et al., 2001; Matsuda et al., 2005; Legate et al., 2006). Parvin-beta and Parvin-alpha appear to negatively regulate the expression of each other (Zhang et al., 2004; Johnstone et al., 2008). Parvin-beta may modulate signalling through ILK as overexpression of Parvin-beta reduced AKT (S473) and GSK3beta (S9) phosphorylation in response to EGF stimulation (Mongroo et al., 2004). Parvin-beta was recently reported to directly interact with AKT (Kimura et al., 2010), which may explain its effects on AKT phosphorylation. Parvin-beta interacts with ARHGEF6 (alpha-PIX), an exchange factor for RAC1, thus implicating Parvin-beta in regulation of RAC signalling downstream of integrin engagement (Rosenberger et al., 2003). Finally, Parvin-beta may affect metabolic pathways through promotion of CDK9-mediated phosphorylation and activation of PPARgamma transcriptional activity in the nucleus (Johnstone et al., 2008). Interestingly, Parvb knockout mice were recently generated. Whilst constitutive Parva null mice feature kidney and cardiovascular defects and die between E10.5 and E14.5 (Lange et al., 2009; Montanez et al., 2009), constitutive Parvb null mice are viable (Wickström et al., 2010), although a detailed phenotypic analysis has not yet been described.

Human Parvin-beta is most closely related to Parvin-alpha [75% identity with Parvin-beta(short) and 67% identity with Parvin-beta(long)] and more distantly to Parvin-gamma [41% identity with both Parvin-beta(short) and Parvin-beta(long)].

No mutations reported to date.

Germline SNPs are identified in the PARVB gene by direct sequencing of PCR products amplified from cDNA prepared from 16 primary ductal adenocarcinomasand adjacent normal mammary gland from the same patient. Two non-synonymous SNPs were identified, W37R, and E175K (Johnstone et al., manuscript in preparation).

Name	Alleles	Location	Base Position†	Amino Acid Position‡	Amino Acid change	No. of Alleles
A98C	A/C	Intron 1	98**	n/a	n/a	3/8
W37R	T/C	Exon 2	252	37	W>R	3/8
D150D	C/T	Exon 5	593	150	D>D	2/32
E175K	G/A	Exon 6	666	175	E>K	2/32
A223A	C/T	Exon 7	812	223	A>A	2/32
G316G^	C/T	Exon 12	1097	318	G>G	2/32
F354F^	C/T	Exon 13	1205	354	F>F	2/32

† Relative to transcription start site
‡ Relative to translation start site
^ Occur as a haplotype
** Relative to splice site

No somatic mutations were found in an analysis of 16 breast adenocarcinomas as presented above (Johnstone et al., manuscript in preparation). According to the C.O.S.M.I.C. online database (Forbes et al., 2008), 171 unique cancer samples have been analysed for alterations in the PARVB gene, with no somatic changes found. A breakdown of the samples analysed is given below.

Cancer Type	No. of Specimens	Reference
Breast	11	Sjöblom et al., 2006
Glioma	23	Parsons et al., 2008
Clear Cell Renal	101	Dalgliesh et al., 2010
Colon	12	Sjöblom et al., 2006
Lung (cell lines)	11	N/A
Pancreas (cell lines)	1	N/A
Mesothelioma (cell lines)	1	N/A
Melanoma (cell lines)	6	N/A
Urinary tract (cell lines)	2	N/A
HNSCC (cell lines)	3	N/A