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ZINC FINGER PROTEINS

     Many proteins utilize zinc ions to stabilize structures, tethering the amino acid chain at four separate points.  Enzymes can also utilize zinc to activate water molecules in a reaction.  Zinc only has one oxidation state (unlike copper and iron).  While many extracellular proteins use disulfide bonds to stabilize their structure, the reducing intracellular environment destabilize these bonds.  As a result, intracellular proteins often utilize zinc to stabilize their structures instead of disulfide bonds (Schwabe, 1994).

     The first discovered regulatory protein which promoted transcription in eukaryotes (TFIIIA) was a zinc finger protein.  Zinc finger proteins are a family of proteins whose loop structures bind ions of zinc (through cysteine and histidine amino acids occurring in conserved positions in the protein) and interact with DNA.

ZINC FINGER
    While transcription regulation most advanced in eukaryotes, some zinc finger proteins in prokaryotes are known.  Because of its simple structure, and dispersal throughout eukaryotes, the zinc finger domain is considered to be among the earliest domains to have evolved.  The cyanobacteria Synechococcus gene smtB encodes a prokaryotic zinc finger protein, similar to sequences in other prokaryotic homologs.  The protein binds zinc and offers protection from the toxicity of environmental zinc.  Mutants are hypersensitive to zinc levels in the environment (Blindauer, 2001).  Cyanobacteria are depicted below.
CYANOBACTERIA

    A prokaryotic zinc finger protein named Ros is divergent from eukaryotic proteins in that there are 9 amino acids in the loop of the finger rather than the usually invariant twelve.  Ros homologs in eubacteria, archebacteria, algae, fungi,  invertebrates, and vertebrates (including humans) can activate both prokaryotic and eukaryotic promoters (Bouhouche, 2000).  Because one of the bacteria which posses Ros (Agrobacterium) can infect plant tissues, it is possible that prokaryotic Ros genes originated through horizontal transfer from eukaryotic plants.  However, Ros genes are not known from plants, horizontal transfer from plants to Agrobacterium is not supported (Bouhouche, 2000; Chou, 1998).  In addition, the diversity of the bacteria which possess Ros homologs indicates that if bacteria received Ros genes from eukaryotes, it would have occurred long ago, even before the origin of mitochondria.  It is also possible that the endosymbiosis event which led to the origin of mitochondria introduced zinc fingers into the proto-eukaryotic lineage rather than the reverse direction of gene transfer (Moreira, 2000).

   Zinc finger proteins are known in all the groups of eukaryotes.  The alga Chlamydomonas uses the zinc finger protein Ccm1 to sense carbon dioxide concentrations (Fukuzawa, 2001).  Trypanosomes have zinc fingers (Espinosa, 2003).  More than 160 zinc finger proteins were described in a study of 13 yeast species (Bussereau, 2004).  Fungi use zinc fingers in formation of fruiting bodies (Masloff, 2002).  Zinc finger proteins in maize can interact with leucine zipper transcription factor (Vincente-Carbajosa, 1997).  Two genes referred to Arabidopsis known as FIS1 and FIS2 function in embryonic development.  FIS2 is a zinc finger protein and FIS1 is homologous to the gene Enhancer of zeste in Drosophila (a member of the Polycomb group) (Luo, 1999).

    Multiple zinc finger proteins are known in every metazoan animal which has been studied (Hemavathy, 2000).  Studying these zinc finger proteins has increased our understanding of how complex animal patterning has evolved.  For example, expression patterns of the zinc finger protein glass indicate that the larval eyes of beetles and flies were derived from the most posterior ommatidia of the adults of their ancestors (Liu, 2004b).   The most abundant gene subfamily of zinc finger proteins (the C2H2 family) in humans (which possess more than 564 paralogous members of this family in their genome), is also widespread in other organisms: yeast possess at least 34 genes, the worm C. elegans possesses 68, and Drosophila 234 genes (Brown, p. 44).  Nematodes possess about 500 transcription factor genes, including about 170 zinc finger proteins. Of the 700 transcription factors known in fruit flies, about half are zinc finger proteins. In the tunicate genome, 566 zinc finger genes are known (Miwata, 2006). In vertebrates, another family of zinc finger proteins, that of thyroid and steroid hormone receptors, has produced many important transcription regulators.  Multiple zinc finger regions can occur in the same protein (as many as 37 regions found in an amphibian protein).

     While many zinc finger proteins are expressed only in very specific tissues, many zinc finger proteins are widely expressed throughout the body such as Zinc Finger Proteins 45, 92, 107, 123, 145, 216, 263, 264, 277, 320, and ZK1.  Some proteins have multiple zinc finger domains; Zinc Finger Protein 175 has 13 domains, Zinc Finger Protein 146 has 10 domains.  There area number zinc finger proteins on chromosome 19 which are not known from mouse or rat genomes and seem to be of recent origin in primates.  Some of the zinc finger sequences in the human genome are pseudogenes,  such as Zinc Finger Protein 204 (OMIM).  Surveys of the intergenic regions in the genomes of humans, flies, worms and yeasts indicate that they contain regions which seem to be sequences of ancestral genes which have long ago lost their function and degenerated.  These pseudomotif regions include zinc finger regions (Zhang, 2002a).  

     Artificial polydactyl zinc finger proteins are even being generated in laboratories to study gene expression in a diversity of organisms (Segal, 2001; Liu, 1997). 

 

     There are more than 700 zinc finger proteins in the human genome.  The largest family of zinc finger proteins is the C2H2 or Kruppel group, a conserved region of about 28 amino acids which uses 2 cysteine and 2 histidine residues to bind zinc.  There are an estimated 700 C2H2 zinc finger proteins alone, making it one of the largest protein families known.  Members of this gene family members may contain additional regions such as KRAB, BTB/POZ, or SCAN (Sander, 2003).  The Kruppel associated box (KRAB) is a conserved region of about 75 amino acids found in about one third of zinc finger proteins known in the human genome.  The region contains multiple zinc-finger motifs (Belleford, 1988).  KRAB transcription factors are only known in vertebrates (Sander, 2003).  The SCAN domain contains 3 α-helices and is only known in vertebrates.  The function of SCAN family members include differentiation, cell growth, and lipid metabolism.  There are 24 SCAN family member genes in the human genome.   In both human and mouse genomes, SCAN genes can exist in tandem arrays, many of which are shared between the two (Sander, 2003). BTB/POZ transcription factors are known in yeast, flies, and mammals (Sander, 2003).  The BTB/POZ domain (which contains broad complex, tramtrak,  bric a brac, and zincfinger regions) is used during development and in proteins which bind actin (Deltour, 1999). ZINC FINGER

GATA

GATA zinc finger proteins are C-X2-C-X17(or 18)-C-X2-C proteins which interact with DNA sequences which contain GATA sequences.  These proteins are known in all eukaryotic kingdoms.  In fungi, they are often involved in nitrogen metabolism and in plants they are often involved in light responses (Teakle, 1998).The GATA proteins can be divided into two subfamilies: GATA1-3 (which function primarily in hematopoeisis) and GATA4-6 (which are expressed in the heart, digestive system, and extraembryonic endoderm).  GATA factors regulate endoderm development in nematodes, flies, and vertebrates (Shivdasani, 2002).  GATA6 is also expressed in the ectoderm, neural tube, and in cells derived from neural crest (Nemer, 2003).   A number of zinc finger transcription factors are involved in the developing placenta including Rex-1 (in the GATA family) (Morasso, 1999).  GATA homologs are expressed in endoderm of diverse coleomates including echinoderms, despite the unique development endoderm of various echinoderm lineages (Hinman, 2003).  The developing endoderm in Amphioxus is indicated in the adjacent image.

gi tract

The GATA family of zinc finger transcription factors is found in all groups of higher eukaryotes.  Unlike other families of eukaryotic transcription factors, it has not undergone significant amplification; only six are known in vertebrates.

 

A number of genes found to control hematopoeisis in fish (including some which cause blood cell numbers to be significantly reduced or absent), belong to the same GATA family of transcription factors which is important in mammalian hematopoeisis.  Mutations in GATA1 disrupt the formation of red blood cells in both fish and mammals (Lyons, 2002).

 

GATA2 is expressed in differentiating blood cells.

 

 

GATA3 binds to enhancers of TCR and other genes.  Mutations cause hypoparathyroidism, sensioneural deafness, and renal dysplasia (OMIM).  GATA3 determines the expression of NeuroD in the differentiation of the auditory neurons of the ear (Lawako-Keali, 2004).

 

GATA4 is required for the response to several stresses by brain and muscle cells.

 

GATA5 functions in the differentiation of cardiac muscle.

 

GATA6 is expressed in smooth muscle (Patient, 2002).

 

Snail

The Snail and Scratch zinc finger families share a region at the C-terminus (which contains 4-5 zinc fingers) which sets them apart from other zinc finger proteins.  In coelomates, Snail family members are critical in the differentiation of mesoderm from epithelia, migration of neural crest cells, and apoptosis (Hemavathy, 2000; Spring, 2002).   Snail and Scratch seem to have arisen from a gene duplication before nematodes.  These genes are only known in metazoan animals and not plants or fungi (Mazanares, 2001).

The Snail family members of zinc finger transcription factors Snail, Escargot, and Worniu function in the developing invertebrate nervous system.   Vertebrate homologs of Snail and Slug are involved in E-cadherin expression and activity of B cells respectively.  In contrast, both mammalian and Drosophila homologs of Scratch are expressed in the developing nervous system (Nakakura, 2001; Mazanares, 2001).    The developing brain of a chick is depicted below.

brain

Snail is essential for gastrulation (Hemavathy, 2004).  In tunicates, the expression of Hrsna is similar to that of its vertebrate homolog snail which is a zinc finger transcription factor involved in the differentiation of mesoderm and body axis formation (Wada, 1999a).

           

Zinc Finger Protein 6 seems to be derived from the same ancestral gene as ZFX and ZFY.

 

Zinc Finger Protein 9 is widely expressed throughout the body, with its highest expression in skeletal (pictured below) and cardiac muscle.  Mutations which expand trinucleotide repeats can cause myotonic dystrophy type 2.

skeletal muscle

The human gene ZFD25 is a C2H2 KRAB protein with 25 zinc fingers (Li, 1999).

 

Zinc Finger Protein 35 is down regulated in some cancers.

 

Zinc Finger Protein 36 binds RNA and single stranded DNA; it represses transcription.

 

Zinc Finger Protein 40 binds to GGGACTTTCC and related sequences in MHC I, Immunoglobulin kappa, interleukin-2 receptor, and beta interferon promoters.  It can also bind to similar sequences in HIV and cytomegalovirus promoters.

 

Zinc Finger Protein 42 is involved in the differentiation of myeloid cells and binds the CD34 promoter.

 

Zinc Finger Protein 43 is most highly expressed in T cells (such as those of a human lymph node pictured below).

lymph node

Zinc Finger Protein 46 has its highest expression in the testes, fetal liver, and hematopoeitic cells. 

 

Zinc Finger Protein 51 is a proto-oncogene which is expressed in the lymphatic system.  The genes it regulates include CD69, CD44, cyclin D2, and CDKN1B.

 

Zinc Finger Protein 74 may be involved in Di George syndrome.

 

Zinc Finger Proteins 75A, 75B (a pseudogene), and 75C are highly conserved in humans, chimps, gorillas, and orangutans.

 

Zinc Finger Protein 85 has its highest expression in the testes (pictured below).

testis

Zinc Finger Protein 89 binds the CACCC box in the promoter of TCR genes and represses the expression of gastrin.

 

Zinc Finger Protein 91 is expressed in all tissues but is expressed at the highest levels in T cells.  The Zinc Finger Protein 91 Family includes Zinc Finger Proteins 96, 97, 98, 99, 100, 104, 105, 108, 110, 111, 112, 113, 114, 118, 119, 120, and 122.  They are all widely expressed but are most highly expressed in T lymphocytes (OMIM).  On human chromosome 19p12-p13.1, there are more than 40 zinc finger genes of the ZNF91 gene family.  Although these genes are not known from non-primates or from prosimians, they are known in all anthropoid primates.  All anthropoid primates studies have a major cluster containing members of the ZNF91 family.  The gene sequences of apes are most highly conserved (Belleford, 1995).

 

Zinc Finger Protein 93 is expressed most in T cells.

 

Zinc Finger Protein 102 is widely expressed but is most highly expressed in cells of T lymphoid lineages.

 

Zinc Finger Protein 103 is expressed in the cerebellum (pictured below) of normal individuals and the cerebrum of Alzheimers patients but not the cerebrum of normal individuals.

cerebellum

Zinc Finger Protein 124 can produce alternate transcripts in different tissues.

 

Zinc Finger Protein 127 (makorin) is an imprinted gene: the maternal copy is methylated while the paternal copy is not. 

Zinc Finger Protein 127 antisense strand has a different expression pattern from the sense strand and is also imprinted.

 

Zinc Finger Protein 133 is widely expressed throughout the body and represses transcription.

 

Zinc Finger Protein 143 is widely expressed throughout the body and has its highest expression in the ovary.  It increases the transcription of snRNA promoters.

 

Zinc Finger Protein 145 regulates the activity of Hox genes in the axial and appendicular skeleton.  Mutations may cause leukemia.  A blood smear from a leukemia patient is given below.

leukemia

Zinc Finger Protein 151 activates cyclin D1 and is repressed by myc.

 

Zinc Finger Protein 161 regulates the expression of interleukin-3.

 

Zinc Finger Protein 165 is expressed at low levels in many tissues.

 

Zinc Finger Protein 169 is most highly expressed in the kidney.

 

Zinc Finger Protein 174 is widely expressed with its highest expression in the gonads.

 

Zinc Finger Protein 177 is expressed in several different tissues and its transcript can be alternately spliced.

 

Zinc Finger Protein 185 is most expressed in the embryonic and adult kidney.

 

Zinc Finger Protein 195 is primarily expressed in the heart, brain, placenta, skeletal muscle, and pancreas.

 

Zinc Finger Protein 198 expression can be a factor in leukemia.

 

Zinc Finger Protein 202 is implicated in a number of cancers.

 

Zinc Finger Protein 215 is an imprinted gene which, when mutated, can cause Beckwith-Wiedeman syndrome.

 

Zinc Finger Protein 219 is expressed in all tissues and an alternate transcript is expressed during fetal development.

 

Zinc Finger Protein 220, also known as MOZ, has C2H3 and CHHC3 domains.  It also possesses an acetyltransferase domain: acetylation is important in gene activation, chromatin structure, and gene inactivation.  It may have a role in exiting the cell cycle.

 

Zinc Finger Protein 231 (Bassoon, mouse homolog) has 2 zinc finger domains, a leucine zipper domain, and several other domains.  It participates in neurotransmitter release in presynaptic axon terminals.  Mutations cause neurodegenerative diseases.

 

Zinc Finger Protein 236 increases its expression when glucose levels are very high.

 

Zinc Finger Protein 239 is widely expressed throughout the body.  It is active in and around the nucleolus and is involved with ribonucleoprotein activity.

 

Zinc Finger Protein 259 is important in rRNA organization in the nucleolus.

 

Zinc Finger Protein 268 is expressed during embryonic development (Gou, 2001).

 

Zinc Finger Proteins 272 and 273 are more highly expressed in white blood cells (a human neutrophil is pictured below) than in other tissues of the body.

neutrophil

Zinc Finger Protein 274 is expressed in many tissues; its protein is active in the nucleolus.

 

Zinc Finger Protein 278 also has a POZ domain.

 

Promyelocytic leukemia zinc finger gene (PLZF) is known in nematodes and several paralogs exist in humans.  It is a member of the BTB/POZ family.  Mutations in humans can cause leukemia (Zhang,1999). 

 

Zinc Finger Protein 288 is involved in hematopoeisis and immune function.

 

ZNF323 possesses 6 zinc fingers and a scan box which is expressed in the multiple embryonic tissues (Pi, 2002).  The SCAND2 gene seems to have arisen from a fusion of an ancestral SCAN gene with cDNA from the C1orf12 gene through retroposition (Dupuy, 2002).

 

The homologous and intronless genes Zfp352 and Zfp353 are associated with LINE1 elements and thus seem to have evolved from retrotransposition (Chen, 2002).

 

ZNF359 and ZFP28 are expressed during the development of the heart, skeletal muscle, lung, kidney, and brain (Zhou, 2002).

 

MAPK are among the most widespread eukaryotic pathways.  ZNF411 may inhibit MAPK pathway, one of the most common eukaryotic signaling pathways (Liu, 2004a).

 

Zinc Finger Protein 463 may be involved in spermatogenesis (as in the testes below).

testis

Double Stranded RNA Zinc Finger

 

Early Growth Response 1 is essential for apoptosis and is involved in cancer suppression.

 

Fanconi Anemia Zinc Finger can cause Fanconi Anemia.  There are 3 alternate transcripts which are expressed only in the testes.

 

General Transcription Factor 111A

 

HELZ is an RNA helicase with a zinc finger domain which unwinds double stranded RNA and is expressed during embryonic development.

 

Kruppel-like factor 4 is expressed in epithelia where its action creates a less permeable epithelial barrier.  Mutations in mice cause substances to leak through epithelial tissues and affected mice die.

 

myc-Associated Zinc Finger Protein MAZ is widely expressed throughout the body and regulates the cell cycle after being induced by myc.

 

A number of zinc finger proteins, such as HFHZ (kruppel-like zinc finger gene) are important in the development of the heart and cardiovascular system  (Zhou, 2002).

 

LF1/EBF-Associated Zinc Finger Protein is widely expressed.  It can be activated by bone morphogen protein and by Olf 1—this transcription factor is involved in different pathways in different tissues.

 

LKLF inhibits T cell proliferation.

 

PEG3 seems to have a role in determining maternal behavior towards young. The Kruppel zinc finger protein PEG3 is imprinted in mice since only the paternal allele is expressed.   Peg1 is also a paternally expressed gene in mice.  Mutations in both of these genes cause deficiencies in maternal behavior such as nurturing, nest building, and pup retrieval, often leading to the death of the young.  When mutated in mice, more than 90% of the young die due to maternal neglect.  The number of neurons in the mother’s brain involved in oxytocin circuits is decreased Human Peg3 is similar in sequence to the gene in mice and is also expressed in the brain (Murphy, 2001; OMIM)

 

Peg3 is also expressed in both cell survival and apoptosis (Murphy, 2001)

 

 

Human ZIM2 is located close to PEG3 (both are zinc finger proteins), the two genes share a common promoter, and both are paternally imprinted in humans.  Comparative analysis of the sequences of other mammals indicates that the common set of exons in these two genes and the common promoter are not the ancestral condition but resulted from a gene fusion event of these two neighboring genes.  Given that ZIM2 is not paternally imprinted in cows or mice, the human paternal imprinting of ZIM2 seems to have resulted from this fusion in the human lineage (Kim, 2004).

 

requiem causes apoptosis.

 

Ribosomal Protein L37 has a zinc finger domain.

 

The RING Finger subfamily of zinc finger proteins is involved in oncogenesis, signal transduction, development, transcription repression, and peroxisome function (OMIM).  The homologs of the yeast protein VPS41 in animals and plants possess a RING-H2 zinc finger.  Mutations in these genes cause abnormal vacuoles and post-Golgi processing (Radisky, 1997).

 

 

Zinc Finger Protein 144 is most highly expressed in the nervous system and in some tumors.  It is conserved in vertebrates and may be a homolog of the genes of the polycomb group in Drosophila.

 

Zinc Finger Protein 147 is induced by estrogen.

 

Zinc Finger Protein 179 is expressed in the brain.

 

PEX10 is needed for the synthesis of peroxisomes.  Mutations cause Zellweger syndrome.

 

Ring Finger Protein 28 interacts with ubiquitin-like proteins and may be involved in the cell cycle.

 

RIZ binds retinoblastoma protein in neurons and the retina.  It is involved in retinoblastoma tumors and perhaps other tumors as well.

 

RLIM is involved in the regulation of the LIM homeodomain.

 

SALL1, when mutated, causes Towns-Brooks syndrome.

 

TIEG is a Zinc Finger Protein which is regulated by TGFb1 and controls cell growth in many tissues.

 

TRIM proteins have 3 zinc finger domains and is involved in development and growth.

 

TRPSI, when mutated, causes craniofacial and skeletal abnormalities.

 

ZBRK1 is downstream of BRCA it its pathway (BRCA is a tumor suppressor gene whose mutations can lead to breast cancer; breast cancer tissue is pictured below).

cancer

ZHX1, ZHX2, and ZHX3 are members of the zinc-finger and homeoboxes (ZHX) family which contain 2 C2H2 zinc finger domains and five homeodomains (Kawata, 2003).

 

Zinc Finger Homeobox 1b has 2 clusters of zinc finger domains, a SMAD-binding domain, and a homeodomain-like sequence.  It is expressed in embryonic development and, when mutated, can cause retardation, epilepsy, and promotes the metastasis of epithelial tumors.

 

ZHX1 has 2 zinc finger domains and 5 central homeodomains.  It has been found in all tissues tested.

 

The Homez homeobox gene contains two leucine zipper domains in addition to three homeodomains.  It is unique to vertebrates and its origin predates the separation of the lineages of bony fish.  Its sequence is similar to that of ZHX homeodomain proteins (Bayarsaihan, 2003).

 

It seems that the zinc finger transcription factor Manx was critical in the evolution of chordate tails, given that its mutation can cause tailless conditions in urochordates and vertebrates (Satoh, 1995).

 

A zinc finger gene in nematodes is required for the asymmetry of cells in blastula embryos of nematodes (Levitan, 1994).

 

ZFX is located on the X chromosome.  While females only have one active copy after X inactivation, males have two (ZFX and ZFY).

ZFY is an autosomal gene in marsupials and does not seem to be involved in sexual determination in them.  The ZFY family has one representative in humans, and two genes in mice(Zfy1 and Zfy2) descended from a duplication of a common ancestral gene (Mahaffey, 1997).

 

ZNFN1a1 is an important gene in the differentiation of lymphocytes.  ZNFN1a2 and ZNFN1a3 are expressed in a variety of tissues.

 

The vertebrate family of Zic genes are homologs of Odd-paired in Drosophila and homologs are known in nematodes (Aruga, 2004).  The Drosophila gene odd-paired functions in development and activates the segment polarity gene wingless.  Its homolog in mammals, Zic2, is also involved in developmental processes, such neurulation in the development of the nervous system. (Nagai, 2000).  The zic family members also have distinctive expression patterns in the cerebellum.  Zic3 is one of the earliest signals in the development of ectoderm and the development of nervous tissue (Nakata, 1997).  Zic genes are also expressed in the developing eye and the foliation of the cerebellum where mutations lead to abnormal folding (Aruga, 2004). Zic proteins are involved in the patterning of the trunk-tail region (Ohtsuka, 2004).

     Zic genes function in the differentiation of neurectoderm and may activate bHLH transcription factors involved in neuron differentiation.  Mutations in Zic genes can cause holoprosencephaly and abnormalities of the forebrain and cerebellum.  In the dorsal neural folds and neural tube, Zic is expressed while the ventral regions express a Gli proteins (Aruga, 2004).  An estimated 1/250 human conceptions suffer from holoprosencephaly although the incidence at birth is far lower (1/16,000) due to the lethality of the condition.  In the most severe condition, the forebrain is not divided into hemispheres and possesses only a single ventricle (Aruga, 2004).

 

Zic 1 is expressed in the cerebellum.  Cells of the cerebellum are depicted below.

cerebellum

Zic 2 is expressed in the dorsal neural tube and mutations cause holoprosencephaly.

Zic3 is expressed at the primitive streak stage of embryonic development, helps to determine the left/right axis, and is involved in lumbosacral and hindgut development.


ZID has both zinc finger and interaction domains.

 

ZXDa and ZXDb are widely expressed throughout the body.

 

Three zinc finger proteins (GLI1-3) are also involved in the Hedgehog signaling pathway and are homologs of the segment polarity gene cubitus interruptus.  Interruptions in this pathway can cause polydactyly with up to 8 digits. (Manouvrier-Hanu, 1999)Three Gli zinc finger transcription factors (Gli1-3) function in the development of the lungs.  Mutations in mice an cause the absence of lungs and abnormal lobation of lungs (Warburton, 1998).. 

 

DAZL is a zinc finger protein which interacts with DAZ family members which function in meiosis in humans and flies (3 gene members are known in humans) (Moore, 2004).

 

The zinc finger gene nlz helps to establish segmentation in the hindbrain (Runko, 2003).

 

ZEB-1/zfh-1 genes are known in vertebrates and invertebrates where they are expressed in a number of tissues including muscle and the CNS (Postigo, 2000).

 

HIC-1 (hypermethylated in cancer) may be a tumor suppressor protein.  The avian homolog represses cyrstallin gene expression.  The form known in mammals possesses a 13 amino acid insertion (Deltour, 1999).

 

In humans, mutations in the SALL1 zinc finger gene cause Townes-Brocks’ syndrome with its resulting deafness, limb, kidney, and genital abnormalities.  Mutations in fly genes spalt and spalt-related also cause genital abnormalities and the inability to detect sound (from the antenna) (Dong, 2003).

 

In fruit flies, the seven in absentia gene affects the development of the R7 photoreceptor cells and mutations cause infertility.  Human homolog HUMSIAH is a target of p53 and may be involved in apoptosis (Nemani, 1996).

 

The small optic lobes gene in flies is expressed in the brain.  The mammalian homolog, Solh, is expressed in the olfactory bulbs (Kamei, 2000).  Human SOLH is the candidate gene for hereditary cataracts with micophthalmia (CATM) (Kamei, 1998).

 

Tex27 is a conserved zinc finger protein in mammals is expressed during spermatogenesis (de Luis, 1999).

BORIS and CTCF are similar 11 zinc-finger proteins.  CTCF is involved in the insulation of chromatin in imprinting.  All known chromatin insulators interact with CTCF.  BORIS is only expressed in the testis and may be a factor involved in the establishment of new methylation patterns in the genes of male germ lines (Loukinov, 2002)

 

Basonuclin is only active in basal keratinocytes (pictured below) and the gonads.   Basonuclin 2 is a conserved vertebrate zinc finger protein expressed in the testis, kidney, uterus, and intestine (Vanhoutteghem, 2004).

basement membrane

Fez is conserved in coleomates.  Studies from zebrafish indicate that it is one of the earliest marker genes expressed in anterior neurectoderm and may regulate Dlx expression (Yang, 2001).

 

     Anti-Muellerian hormone is a member of the TGF-B family which is required for male development (without which they develop as pseudphermaphrodites).   Females exposed to AMH undergo partial sex reversal.  Four transcription factors are known to bind to the AMH promoter: SF-1, WT1, SOX-9, and GATA-4 (Vaiman, 2000).  WT1 possess four zinc finger domains and mutations are involved in four types of disorders: WIlms tumor, WAGR syndrome, Frasier Syndrome, and Denys-Drash Syndrome.  All of these syndromes may include some aspects of sex reversal.  SF-1 and WT1 are also involved in the production of the original undifferentiated gonad (Vaiman, 2000).

 

YY2, a duplicate of the zinc finger gene YY1, was generated in placental mammals through retroposition (Luo, 2006).

Mutations in the zinc finger gene hairless can cause the absence of hair (alopecia universalis) in both humans and mice (Ahmad, 1998).

 

The zinc-finger protein sequoia affects the branching patterns of axons and dendrites (Brenman, 2001).

 

New zinc finger domains have been located in genes such as dystrophin which seem to mediate protein-protein interactions (Ponting, 1996).