Walsh: metallothionein inhibition: metalloproteinase, glutathione-S-transferase

[Guest guest]

MT = metallothionein

TIMPs = tissue inhibitors of MPs

gshST = glutathione-S-transferase

Woody e-penned that "The metalloproteinase is a MT modulator.

It is apparently coded on the X

Chromosome right next to the locus for night blindness. Might

want to check that out a little."

Medline quickly revealed that humans have a goodly number of metalloproteinase

genes (on a number of chromosomes), and that the first such gene discovered

(way back in 1986) is indeed very close to several genes relating to night

blindness, retinitis pigmentosa, etc.

If Walsh's "low metallothionein" findings are replicated and "generally

true", then there seem to be at least two major candidates for inducing

low MT: the TIMP family of genes, and the gshST family of genes.

Furthermore, irregularities and alleles of gshST genes and of TIMP genes

are already described and provide a basis for much interindividual variation,

especially when manifested through a complex pathway such as MT gene-expression

and the environmental variables influenced by MT levels.

An attachment herewith contains abstracts (a) about chromosomal locations

of TIMP genes and, to some extent, their disease associations, and (

about an X-chromosome TIMP implicated in night blindness, a factoid with

possible relevance to Megson's findings.

The attachment is 14 pages in length, contains some gems, and lots

of other info for persons wanting an overview of genomic TIMP locations.

As I was sending the attachment, I saw that it is appx 500k, so I cancelled

that post. If someone wants the file, write me off list and request the

"metalloproteinase" file.

Here is several tidbits from the attachment:

Genomics 1994 May 15;21(2):337-43

A 1.8-Mb YAC contig in Xp11.23: identification of CpG

islands and physical

mapping of CA repeats in a region of high gene density.

MP, Nemeth AH, L, Raut CP, Weissenbach

J, Davies KE

Institute of Molecular Medicine, Radcliffe Hospital,

Headington, Oxford.

The genes ARAF1, SYN1, TIMP, and PFC are clustered within

70 kb of one another,

and, as reported in the accompanying paper (J. Knight

et al., 1994, Genomics 21:

180-187), at least four more genes map within 400 kb:

a cluster of Kruppel-type

zinc finger genes (including ZNF21, ZNF41, and ZNF81)

and ELK-1, a member of the

ets oncogene superfamily. This gene-rich region is of

particular interest

because of the large number of disease genes mapping

to Xp11.23: at least three

eye diseases (retinitis pigmentosa type 2, congenital

stationary night blindness

CSNB1, and Aland Island eye disease), Wiskott-Aldrich

syndrome, X-linked

nephrolithiasis, and a translocation breakpoint associated

with synovial

sarcoma...

11: Am J Hum Genet 1993 Jan;52(1):71-7

Manifestations of X-linked congenital stationary night

blindness in three

daughters of an affected male: demonstration of homozygosity.

Bech-Hansen NT, Pearce WG

Department of Paediatrics, Alberta Children's Hospital,

Calgary, Canada.

X-linked congenital stationary night blindness (CSNB1)

is a hereditary retinal

disorder in which clinical features in affected males

usually include myopia,

nystagmus, and impaired visual acuity. Electroretinography

demonstrates a marked

reduction in b-wave amplitude. In the study of a large

Mennonite family with

CSNB1, three of five sisters in one sibship were found

to have manifestations of

CSNB1. All the sons of these three sisters were affected.

Each of the two

nonmanifesting sisters had at least one unaffected son.

Analysis of Xp markers

in the region Xp21.1-Xp11.22 showed that the two sisters

who were unaffected had

inherited the same maternal X chromosome (i.e., M2).

Two of the daughters who

manifested with CSNB had inherited the other maternal

X chromosome (M1). The

third manifesting sister inherited a recombinant X chromosome

with a crossover

between TIMP and DXS255, which suggests that the CSNB1

locus lies proximal to

TIMP. One of the affected daughters' sons had inherited

the maternal M1 X

chromosome, a finding consistent with that chromosome

carrying a mutant CSNB

gene; the other affected sons inherited the grandfather's

X chromosome (i.e.,

P). Molecular analysis of DNA from three sisters with

manifestations of CSNB is

consistent with their being homozygous at the CSNB1 locus

and with their mother

being a carrier of CSNB1.

13: Genomics 1992 Apr;12(4):632-8

Physical linkage of the A-raf-1, properdin, synapsin

I, and TIMP genes on the

human and mouse X chromosomes.

Derry JM, Barnard PJ

MRC Molecular Neurobiology Unit, MRC Centre, Cambridge,

United Kingdom.

Genes encoding the neuron-specific phosphoprotein synapsin

I (SYN1), the

glycoprotein tissue inhibitor of metalloproteinases

(TIMP), the proto-oncogene

A-raf-1 (ARAF1), and properdin (PFC), a positive regulator

of the alternative

pathway of human complement, lie within a conserved

synteny encompassing the

proximal short arm of the human X chromosome (Xp21.1-p11)

and the centromeric

end of the mouse X chromosome (A1-A5). We have used a

mouse interspecific cross

to demonstrate genetic linkage of Syn-1, Timp, and Araf

and also show physical

linkage, with Timp lying only 10 kb from Araf, within

an intron of the Syn-1

gene. Detailed restriction mapping shows that Timp is

transcribed in the same

direction as Araf but in the opposite direction to the

Syn-1 gene. Analysis of

the corresponding region of the human X chromosome indicates

a similar

arrangement and in addition shows that the properdin

gene lies within 5 kb of

the 5' end of the synapsin I gene.

Exciting "stuff"!