DNA encoding a human tubby homolog

Details DNA encoding a human tubby homolog DNA encoding a human tubby homolog

1997-03-06

2001-03-20

Draper, Garnette D. (Department: 1647)

Organic compounds -- part of the class 532-570 series

Organic compounds

Carbohydrates or derivatives

C536S023510, C536S063000, C435S069100, C435S069400, C435S069500, C435S006120, C435S252300, C435S320100

Reexamination Certificate

active

06204372

ABSTRACT:

FIELD OF THE INVENTION
This invention relates to nucleic acid and amino acid sequences of a novel human tubby homolog and to the use of these sequences in the diagnosis, prevention, and treatment of appetite and eating disorders, especially anorexia, cachexia and obesity.
BACKGROUND OF THE INVENTION
Appetite and eating are ultimately under the control of the brain, specifically the hypothalamus and cerebral cortex; however, psychological, social, and genetic factors also affect this area of human behaviour. The cerebral cortex receives positive signals from the feeding center which is located in the ventrolateral nucleus of the hypothalamus. The feeding center stimulates eating until it is inhibited by the satiety center which is located in the ventromedial hypothalamus. Chemically, increased plasma glucose, insulin, catecholamines, and beta-adrenergic stimulation are known to inhibit the eating behaviour.
Obesity results from the disregulation of one or more of the controls or factors which influence eating. Generally, obesity is defined as an excess of adipose tissue; and clinically, it is defined as that amount of adiposity that imparts a health risk. Even mild obesity, at 20% over desirable weight according to standard height-weight charts, may increase the risk for disease and premature death.
Obesity has a major impact on human health and the US healthcare system through its effects on cardiovascular disease, diabetes mellitus, and hypertension. Although less well known, gall bladder problems; hyperlipidaemia; Alstrom, Bardet-Biedl, Cushing's, Froehlich's, and Prader-Willi syndromes; and cancers, such as craniopharyngioma and hypothalamic, pituitary, and islet cell tumors, also fall into this category. Recent studies indicate that lipophilic mutagens stored in fatty tissues such as mammary gland adipose cells may serve as the primary source for p53 mutations that result in cancers of those tissues.
The mouse obesity gene, tubby (tub), first reported as an autosomal recessive mutation has been cloned (Coleman, D. L. and E. M. Eicher (1990) J. Hered. 81:421-427; Noben-Trauth K. et al. (1996) Nature 534-38; and Kleyn, P. W. et al. (1996) Cell 85:281-90). Although different length splice variants are reported for the tub molecule, the mutant gene is abundantly expressed in hypothalamus and has a G−>T transversion which affects the 44 amino acids at the carboxyterminus. The hydrophilicity of the tub protein (pI=9.2) and the absence of signal or transmembrane motifs suggest cytosolic localization. The tub protein has two sets of serine residues separated by acidic residues which may function as a hinge, and two potential glycosylation sites, N
205
and N
426
.
The tub mutation has been associated with maturity onset diabetes, insulin resistance, progressive retinal degeneration and hearing loss. Although zinc binding site motifs are not present, tub has some homology to mouse phosphodiesterase, and Noben-Trauth et al. suggest that sensory deficits may be associated with cGMP induced, phosphodiesterase mediated apoptotic activity.
Because of the numerous correlations between obesity, health, and healthcare, polypeptides related to tubby and the polynucleotides encoding them satisfy a need in the art by providing compositions useful in the diagnosis, prevention, and treatment of appetite and eating disorders, especially anorexia, cachexia, diabetes, and obesity.
SUMMARY OF THE INVENTION
The present invention features a novel human tubby homolog, hereinafter designated NHT, and characterized as having similarity to the mouse tub gene (GI 1279766, SEQ ID NO:3) and the human tub homolog (GI 1305497, SEQ ID NO:4).
Accordingly, the invention features a substantially purified NHT having the amino acid sequence shown in SEQ ID NO:1.
One aspect of the invention features isolated and substantially purified polynucleotides that encode NHT. In a particular aspect, the polynucleotide is the nucleotide sequence of SEQ ID NO:2.
The invention also relates to a polynucleotide sequence comprising the complement of SEQ ID NO:2 or variants thereof. In addition, the invention features polynucleotide sequences which hybridize under stringent conditions to SEQ ID NO:2.
The invention additionally features nucleic acid sequences encoding polypeptides, oligonucleotides, peptide nucleic acids (PNA), fragments, portions or antisense molecules thereof, and expression vectors and host cells comprising polynucleotides that encode NHT. The present invention also features antibodies which bind specifically to NHT, and pharmaceutical compositions comprising substantially purified NHT. The invention also features agonists and antagonists of NHT and methods for using the protein, agonists and antagonists in the treatment of appetite and eating disorders.


REFERENCES:
patent: 5646040 (1997-07-01), Kleyn et al.
patent: 6114502 (2000-09-01), North et al.
patent: WO 97/02048 (1997-01-01), None
Coleman, DL and Eicher, EM, “Fat (fat) and tubby (tub): two autosomal recessive mutations causing obesity syndromes in the mouse”J Hered81 (6):424-427 (1990).
Noben-Trauth, K et al., “A candidate gene for the mouse mutation tubby”Letters to Nature380:534-538 (1996) (GI 1279766).
Kleyn, PW et al., “Indentification and Characterization of the Mounse Obesity Gene tubby: A Member of a Novel Gene Family”Cell85:281-290 (1996) (GI 1305497).
Database EMBL—EMSTS, Entry HS615299, Acc. No. G17615, Mar. 7, 1996, Myers, R.M.: “human STS SHGC-1217 clone pg-71”.

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