List of Diseases

ENZYME DEFECTS

    Smith-Lemli-Opitz Syndrome- Loss of activity

     Homocysteinuria – defect in coenzyme binding

     Gout – substrate and effector binding defects

     Porphyria Cutanea Tarda – kinetic constant defects

     Tay Sach Disease – accessory protein defect

MEMBRANE PROTEIN DEFECTS

     Familial Hypercholesterolemia – LDLR defect                       

      Niemann Pick disease – lysosomal transporter defect

      Sitosterolemia – an ABC transporter defect

      Tangier’s Disease – another ABC transporter defect                        

RECEPTOR DEFECTS

     McKune-Albright syndrome – G protein defect

     Night Blindgess - Rhodopsin

     Acromegaly- Growth hormone

     Psuedohyperparathyroidism type A

CHANNEL DEFECTS        

    Cystic Fibrosis

    Paramyotonia congenita

    Arrhythmias

STRUCTURAL GENE DEFECTS

    Osteogenesis Imperfecta – Collagen defect

    Marfan’s Syndrome – Microfibril defect

DEVELOPMENTAL  PROTEIN DEFECTS

    Synpolydactyly – HOX gene defect

    Holoproencephaly – Hedgehog gene defect

    Colon cancer –Wnt-1 signaling, APC, b-catenin  

Familial Hypercholesterolemia – LDLR defect 

Familial hypercholesterolemia (FH) is a genetic disorder with an incidence of 1 in 500 individuals. It is an autosomal dominant disease and can lead to  arteriosclerosis, coronary artery disease and myocardial infarctions. Heterozygous individuals exhibit about double the normal level of cholesterol whereas homozygotes exhibit up to six-times the normal level of cholesterol.  FH arises due to defects in the LDL receptor. 

The LDL receptor is a membrane protein that starts in the rough ER, moves to Golgi network for further processing and is then transported to the cell membrane that joins a cluster of other LDL receptors in a coated pit. The clustering is essential in normal uptake of LDL particles through endocytosis. In the endosome formed, a change in the pH occurs that releases the receptor from the LDL particle. While the receptor is recycled, the LDL particle is transported to lysosomes where it is degraded into various products including free cholesterol. 

The LDL receptor is a 160 kD protein that has six functional domains. It has a signal sequence at its amino terminal, a ligand-binding domain, an epidermal growth factor precursor homology domain, a clustered O-linked sugar domain, a transmembrane domain and a cytoplasmic domain at the carboxy terminal. The ligand-binding domain is responsible for interacting with components of LDL including apolipoprotein E and apolipoprotein B. The EGF precursor homology domain releases the bound ligand through an acid-dependent conformational change. The transmembrane domain anchors the receptor in the cell membrane, and the cytoplasmic domain targets the receptor to the coated pits.

FH is autosomal dominant and follows transmission of Mendelian genetics. Expression is equal in both males and females, but males are more affected clinically. The gene for familial hypercholesterolemia has been located near the tip of the short arm of chromosome 19 (19p13.2-19p13.12). The gene is relatively large (45 kilobases) and contains 18 exons and 17 introns. An interesting feature of this gene is that it shares DNA coding blocks (13 exons) with the genes for blood clotting factors IX, X and protein C, C9 complement, and epidermal growth factor. The protein product has six different domains and contains 860 amino acids.

Gene Card Entry

Osteogenesis Imperfecta (OI) Type1 is a generalized connective tissue disorder that results from reduced amounts of normal collagen I. The disease is characterized by brittle bones and multiple fractures, usually from minimal trauma. The frequent fractures begin at birth however this frequency diminishes with increasing age, after puberty. Fractures often increase again following menopause in women and after the sixth decade in men. Fortunately these fractures heal rapidly and without deformity. Affected individuals usually have normal teeth, and normal or near-normal stature. They also present with blue sclera at birth, which may remain intensely blue throughout life. For some affected individuals, the intensity of the blue fades by adulthood. Hearing loss is fairly common, resulting from fixation of bones of the middle ear. OI Type 1 is dominantly inherited and in most cases, results from "functional null" alleles of COL1A2 on chromosome 17 or COL1A2 on chromosome 7. There is currently no known medical treatment for OI Type I. An effective treatment would have to decrease the frequency of bone fracture or increase bone density. Increasing the production of procollagen I would probably be an effective goal for gene therapy. However as the frequency of fractures decreases with increasing age, patients with OI Type I do have successful outcomes.

Pathway

In order to understand how mutations in collagen genes cause the symptoms of OI Type 1 it is useful to first discuss the normal structure of collagen. Collagen is the most common protein in the body and is found in almost all of its structural components, including bone, cartilage, ligaments, and tendons. As many as 18 different types have been described in the human body, and of these, Collagen Type I is one of the most widely distributed.

OI Type 1, which results from a defect in the production of Type I Collagen, can therefore have serious phenotypic consequences. Each Collagen Type I molecule is a trimer composed of two identical alpha1(I) chains and one alpha 2(I) chain. These three chains are first assembled into a triple-helix called procollagen, and are then modified via post-transcriptional proteolytic cleavage to yield a mature collagen fibril. Although the alpha1 and alpha 2 chains differ from each other in some respects, they both contain an amino acid triplet repeat (Glycine-X-Y)n (n>300). This repeated motif is important in stabilizing the structure of collagen, and mutations affecting the repeat can cause a failure of the collagen molecules to correctly assemble, leading to various types of OI.. Cohn et al. found that substitution of cysteine for glycine within the carboxyl-terminal of the alpha 1 chain of type I collagen produces mild osteogenesis imperfecta (Cohn et al, 1988).

The 2:1 ratio of alpha1(I) to alpha 2(I) chains is also an essential feature of the collagen trimer. Mutations affecting the amount of alpha1(I) or alpha 2(I) produced will also have serious consequences for the amount of collagen that can be synthesized in the cell. OI Type 1 results from a defect in the gene COL1A1, which codes for the pro-alpha1(I) peptide. Barsh et al. (1982) found that individuals with OI Type 1 produced only equimolar amounts of pro-alpha1 and pro-alpha 2, in contrast to the expected 2:1 ratio. They also observed that individuals with OI Type I produced half normal levels of Type I procollagen, leading researchers to believe that a defect in the COL1A1 gene leads to half-normal production of pro-alpha1; the trimer assembly is consequently limited by the half-normal amount of pro-alpha1 produced. They also found that the excess amount of pro-alpha 2 is not secreted but instead contributes to an increased level of intracellular degradation. This disease is thus an example of haploinsufficieny, where one non-functional allele leads to a quantitative insufficiency of the protein product.

Osteogenesis Imperfecta Type I is inherited as an autosomal dominant trait. Penetrance of certain traits associated with the condition differs. Penetrance of blue sclerae is 100 percent while penetrance of hearing loss is age dependent (Garretsen & Cremer, 1991). The disease gene apparently seems to be linked to either COL1A1 or COL1A2 locus (Sykes et. al, 1986). OI type IV segregated with COL1A2, while a majority of OI type I pedigrees segregated with COL1A1 and some with COL1A2 (Sykes et al., 1990).

The most common genetic features of OI type I is the typical 'functional null' alleles (Byers, 1993). A variety of mutations may be indicated in the mechanism by which production of pro-alpha-1(I) chains is diminished; such as deletion of allele, promoter and enhancer mutations, splicing mutations, premature terminations, and other mutations inhibiting proper assembly of the pro-alpha-1(I) chains to assemble into molecules. Less commonly abnormal procollagen I molecules can also produce OI Type 1 phenotype (Nicholls et al., 1984) as well as substitutions of cysteine for glycine within the triple helical domain of the alpha-1(I) chain at residue 94 (Byers, 1993) produce mild forms of OI.

In women with severe post-menopausal osteoporosis thorough personal and family history might reveal OI type 1, so genetic testing on the basis of linkage could be made. However, diagnosis is difficult since here it involves both clinical and genetic aspects, and the disease does not manifest in a manner distinguishable from general osteoporosis. Usually, demonstration of reduced synthesis of procollagen I by dermal fibroblasts is indicative of the disease.

According to OMIM, no treatment of OI type I is known to decrease the frequency of bone fractures or increase density. However, the rate of fractures decreases with increasing age and or with a placebo effect. Fractures in OI are treated with standard orthopedics and show to heal rapidly without deformity. Regular hearing evaluations in adolescents are recommended, as well as estrogen and progesterone replacement and adequate calcium supplementation for post-menopausal women. More recently, Bembi et. al. (1997), reported that children who were treated with pamidronate showed a reduced fractures over 22-29 months of treatment. Pamidronate is a bisphosphonate which is thought to inhibit osteoclastic bone resorption.

As OI Type I is inherited in an autosomal dominant manner, the risk to affected individuals having affected offspring is 50%, although the effects of incomplete penetrance of the different traits may reduce this risk. If a proband presents with Type I OI it is recommended that family members consider genetic counseling and testing; thus proper precautionary measures to decrease the risk of multiple fractures can be taken.

Gene Card Entry

NYU School of Medicine; Roxanne C. Abder, Angela Yim, and Terence Friedlander

Barsh, G. S.; David, K. E.; Byers, P. H. : Type I osteogenesis imperfecta: a nonfunctional allele for pro-alpha-1(I) chains of type I procollagen. Proc. Nat. Acad. Sci. 79: 3838-42, 1982.

Bembi, B.; Parma, A.; Bottega, M.; Ceschel, S.; Zanatta, M.; Martini, C.; Ciana, G. : Intravenous pamidronate treatment in osteogenesis imperfecta. J. Pediat. 131: 622-625, 1997.

Byers, P. H. : Osteogenesis imperfecta. In: Royce, P. M.; Steinmann, B. : Connective Tissue and Its Heritable Disorders: Molecular, Genetic, and Medical Aspects. New York: Wiley-Liss (pub.) 1993. Pp. 317-350.

Cohn, D. H.; Apone, S.; Eyre, D. R.; Starman, B. J.; Andreassen, P.; Charbonneau, H.; Nicholls, A. C.; Pope, F. M.; Byers, P. H: Substitution of cysteine for glycine within the carboxyl-terminal telopeptide of the alpha1 chain of type I collagen produces mild osteogenesis imperfecta. J. Biol. Chem. 263: 14605-14607, 1988.

Garretsen, T. J. T. M.; Cremers, C. W. R. J. : Clinical and genetic aspects in autosomal dominant inherited osteogenesis imperfecta type I. Ann. N.Y. Acad. Sci. 630: 240-248, 1991.

Gelehrter, T., Collins, F., Ginsburg, D. Principles of medical genetics. Baltimore: Williams & Wilkins, 1998 pp 143-7

Sykes, B.; Ogilvie, D.; Wordsworth, P.; Anderson, J.; Jones, N. : Osteogenesis imperfecta is linked to both type I collagen structural genes. Lancet II: 69-72, 1986.

Sykes, B.; Ogilvie, D.; Wordsworth, P.; Wallis, G.; Mathew, C.; Beighton, P.; Nicholls, A.; Pope, F. M.; Thompson, E.; Tsipouras, P.; Schwartz, R.; Jensson, O.; Arnason, A.; Borresen, A.-L.; Heiberg, A.; Frey, D.; Steinmann, B. : Consistent linkage of dominantly inherited osteogenesis imperfecta to the type I collagen loci: COL1A1 and COL1A2. Am. J. Hum. Genet. 46: 293-307, 1990.

Marfan's Syndrom – Microfibril defect 

Marfan Syndrome was discovered almost a century ago by Dr. Antoine Bernard Marfan. Because it is a connective tissue disorder, it affects tendons, ligaments, blood vessel walls, cartilage, heart valves and many other structures. It is an inherited (autosomal dominant) disorder, caused by a defective gene involved with the production of fibrillin that makes up part of connective tissue in the body. In recent years, the molecular biology and genetics of this disease have become increasingly understood. New advances have paved the way for earlier and more accurate diagnoses, better estimations of prognoses, and more effective treatment of the syndrome.

The molecular basis of Marfan Syndrome is abnormal fibrillin synthesis.  Studies have shown that not only a clear link between levels of microfibril deposition and MFS but an actual correlation between the levels of deposition and the severity of the disease. 

Marfan's syndrome results from mutations in the extracellular protein fibrillin which is an integral constituent of the non-collagenous microfibrils of the extracellular matrix. Fibrillin, a 350 kD glycoprotein which is assembled into microfibrils as part of the extracellular matrix.

The Marfan Syndrome (MFS) is an autosomal-dominant, heritable connective-tissue disorder. Fibrillin is synthesized by fibroblasts, smooth muscle cells, and other cell types and is encoded by a gene of approximately 110 kb. Studies have shown that 75% of its 65 exons are homologous to either epidermal growth factor (EGF) or transforming growth factor B-binding protein (TGFB-bp) (Dietz and Pyeritz 1995). There are two fibrillins, with fibrillin-1 is encoded by FBN1 on human chromosome 15q21, and fibrillin-2 encoded by FBN2 on 5q23. Dietz and Pyeritz (1995) demonstrated that mutations in FBN-1 result in MFS. Kainulainen et al. (1994) found that mutations in exons 24-30, which contains the longest stretch of EGF repeats, have particularly severe effects, which are fatal in the neonatal period.

Gene Card Entry

References

NYU School of Medicine; Lynn Kessler, Jamie Chu, William Malone and Helen Ding

Synpolydactyly – HOX gene defect 

Synpolydactyly (SPD) is a genetic disorder that results from mutations in one of the HOX genes. The phenotypes are shown in the pictures below, which usually involves developmental disorders in the fingers and toes resulting in fusion and malformation.

Pathway

HOX genes in humans are divided into 4 clusters: HOXA, HOXB, HOXC, and HOXD. Each cluster is divided into 13 positional loci that are identified from 1 to 13 and result in individual genes. The positional number 1 to 13 indicates the location the gene is expressed with respect to an anterior-posterior and proximal-distal axis where 1 is anterior or proximal and 13 is posterior or distal. That is, the lower the number is, the closer towards the embryonic anterior or proximal region the gene is expressed and vice versa. Because of this positioning, all genes in a given cluster are termed colinear. Not all positions are present in each cluster. For example, in cluster HOXA, loci 8 and 12 are absent, in cluster HOXB, loci 10 to 13 are absent, in cluster C, loci 1 to 3 and 7 are absent, and in cluster HOXD, 2 and 5 to 7 are absent. The SPD condition occurs as a result of mutations in the HOXD13 gene. The mutation involves an extra polyalanine stretch in the N-terminal region. The longer the stretch, the more severe the condition.

Structure

HOX genes share a common domain which is the HOMEODOMAIN, as a result, the HOX genes are referred to as homeotic genes. There are 11 HOXA genes, and 9 HOXB, HOXC, and HOXD genes; or a total of 38 HOX genes. The DNA sequence that codes the homeodomain is a highly conserved 180-base pair sequence termed the HOMEOBOX. The homeodomain is a helix-turn-helix structural motif that is common to DNA binding proteins, such as transcription factors. 

Genetics

The condition appears to be semidominant in that the malformations are more severe in the homozygotes than in heterozygotes.  

Gene Card Entry

References