Organic compounds -- part of the class 532-570 series – Organic compounds – Carbohydrates or derivatives
Reexamination Certificate
2000-11-08
2003-11-04
Nolan, Patrick J. (Department: 1644)
Organic compounds -- part of the class 532-570 series
Organic compounds
Carbohydrates or derivatives
C435S069100, C435S320100, C435S325000
Reexamination Certificate
active
06642370
ABSTRACT:
BACKGROUND
1. Field of the Invention
The present invention is related to the field of inherited immunological disorders and to the discovery of a genetic mutation as a causative factor in a disorder. The invention also relates to genetic screening for inherited disease and in particular for a marker for familial recurrent arthritis.
2. Description of Related Art
Juvenile idiopathic arthritis (JIA), also known as juvenile rheumatoid arthritis (JRA), is an autoimmune disorder comprising a heterogeneous collection of chronic arthritis of childhood (Fink et al., 1995
, Pediatr Clin North Am
42:1155). This disease is common and affects 1-3 children per 1000. The pathogenesis of JIA as a whole is poorly understood, although genetics has been proposed to play a causative role. (Murray et al., 1997
Arch Dis Child
77:530; Moroldo et al., 1998
, Arthritis Rheum
41:1620; Rossen et al., 1980
, J. Clin Invest
65:629; Rossen et al., 1982
, Human Immunol
4:183). For pauciarticular onset JIA, in which the arthritis is limited to 4 or fewer joints during the first 6 months of disease, both family and population-based studies have revealed linkage and association with specific HLA alleles and disease. Associations with other immune complex molecules are also described (Heward and Gough, 1997
, Clin Sci
93:479). There is, in addition, a striking gender effect for pauci-onset, with a ratio of approximately 8 to 1 girls to boys. Taken altogether the evidence for genetic predisposition to pauci-onset JIA is strong. However, a single causative gene has yet to be identified.
JIA is similar to other autoimmune disorders in that each appears to arise from complex genetic and environmental interactions (Heward and Gough, 1997; Vyse and Todd, 1996
, Cell
85:311). Delineation of these factors and their mechanisms of action is ultimately critical to an understanding of the causes of the destruction of the body's own tissues. One approach to the genetic dissection of these complex disorders is positional cloning of predisposing genes within kindreds who demonstrate a simpler inheritance pattern, a strategy which has been successful in mapping and cloning genes involved in common diseases such as psoriasis (Tomfohrde et al., 1994
, Science
264:1141), familial breast cancer (Hall, J M, et al., 1990
, Science
250:1684) and early onset Alzheimer's disease (St. George-Hyslop et al., 1992
, Nat Genet
2:330).
The present inventor has described a new disorder that occurs in a subset of patients diagnosed as having juvenile idiopathic arthritis. This disorder has been termed “familial recurrent arthritis” or “FRA,” and was identified in a single large family originally carrying the diagnosis of JIA. FRA differs from “classic” JIA in several ways, but most notably in its striking pattern of dominant inheritance, in the pyogenic component of the joint swelling, and in the association with cutaneous findings. A genome wide linkage scan identified a 20 cM region within 15q22-24 most likely to harbor the predisposing gene.
Another disorder with striking similarity to FRA has been reported (Lindor et al., 1997, Mayo
Clin Proc
72:611). The authors reported a single extended family with autosomal dominant transmission of a disorder characterized by pyogenic sterile arthritis, pyoderma gangrenosum, and severe cystic acne which they referred to as “PAPA syndrome”. Like FRA, PAPA syndrome patients presented with acute inflammations which responded to steroid treatment, and laboratory findings were negative. Nine out of ten affected individuals in the PAPA syndrome family were reported to have arthritis in one to three joints, with age of onset varying from one to 16 years of age. Dermatological manifestations were variously found including pyoderma gangrenosum and severe cystic acne with onset at 11 years of age. The PAPA family was also reported to be karyotypically normal, and preliminary genotyping detected no linkage to the HLA region. From this, and given the recent onset of cystic acne in the proband FRA1-1, it is concluded that FRA and PAPA syndrome are likely the same disorder.
A further disorder has been described as “streaking leukocyte factor” (Jacobs and Goetzl, 1975
, Pediatrics
56:570). The description of this disease appears very similar, if not identical to FRA and PAPA syndrome, as the patient described had a history of sterile pyarthrosis and cutaneous inflammation and ulceration since the second year of life, with no increased incidence of infections of any kind. Family history of the disorder, however, was not reported. Interestingly the authors reported partial purification of a serum factor (MW 160 kd) which enhanced the random migration of purified normal human neutrophils or mononuclear leukocytes but did not appear to affect chemotaxis.
There is still a need, however, to identify and isolate the specific gene or genes that are involved in familial recurrent arthritis (FRA) and related disorders in order to provide means of diagnosis and management of the disorders, and to provide insights into the pathogenesis of the autoimmune joint destruction that is symptomatic of these and other autoimmune inflammatory conditions.
SUMMARY
The present disclosure includes the identification of a gene encoding the CD2 binding protein, CD2BP1, as the inherited factor associated with familial recurrent arthritis. In addition, mutant alleles of CD2BP1 are identified as a causative factor in the disorder. The invention also includes isolated nucleic acid molecules that encode mutations in the gene encoding CD2BP1, and particularly isolated genes that encode an amino acid sequence comprising the sequence of SEQ ID NO:2, and a composition including a partially purified protein encoded by the nucleic acid molecules. The invention also includes isolated nucleic acid molecules that include the nucleic acid sequence of SEQ ID NO:1, including expression vectors and host cells transfected with such vectors.
The present disclosure also includes methods of diagnosing an immune disorder in a subject comprising detecting a mutation in a CD2BP1 gene allele in a subject, and methods of diagnosis familial recurrent arthritis comprising detecting a gene allele comprising the sequence of SEQ ID NO:1.
Another aspect of the present disclosure is methods of screening for agents that modify an immune response in cells, and in organisms in which certain cells express a CD2BP1 with a mutation including a E250Q mutation. As used herein, a term such as E250Q denotes a mutation in a protein sequence at the position of amino acid 250. The first letter is the one letter designation of the naturally occurring amino acid (glutamic acid, E) and the last letter is the one letter designation of the amino acid that is substituted (glutamine, Q). Such assays typically include contacting cells or tissues with an agent suspected of modifying an immune response, measuring an indicator of immune response, and comparing that measurement to the same immune response indicator in a control cell or tissue under comparable conditions in the absence of the agent. A difference in the measured response in comparison to the measured control is indicative of an agent that modifies an immune response. It is understood that an agent that modifies an immune response may inhibit or enhance the immune response.
Preferred cells for use in the described assays would include immune cells such as T-cells or NK cells for example, and would also include cells or tissues that include cells that express CD2 or even CD15 expressing cells, either naturally occurring cells, or cells that have been engineered to express recombinant CD2 or CD15.
One may use any immune response assay known in the art, and particularly assays known to involve CD2. Such assays would include, but are not limited to T-cell rosetting, calcium flux, I1-2 production and cytolytic activity.
Another aspect of the disclosure is methods of screening for an agent that modifies an interaction of CD2 with a mutant CD2BP1, preferably a CD2BP1 protein with a E250Q mutation. Binding assays may inc
Nolan Patrick J.
Texas Scottish Rite Hospital for Children
Vinson & Elkins L.L.P.
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