Medical Disease Genetics

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HUMAN DISEASE GENETICS

Contents

Section 1 Title: The Genes of Osteogenesis Imperfecta 3

Section 2 Title: Pathogenesis of Myotonic Dystrophy Type 1 and Type 2 6
Section 3 Title: Huntington Disease Genetics 8

Section 4 Title: The major forms of Glycogen Storage Disease types I, III and IX 11

Section 1 Title: The Genes of Osteogenesis Imperfecta (word count = 568) Osteogenesis Imperfecta (OI) is caused by different genes; COL1A1, COL1A2, CRTAP and LEPRE1. Each gene giving rise to a particular phenotype. OI is characterised by tendency to fracture due to brittle bones, bone curvature and short stature. Osteogenesis Imperfecta has a birth prevalence of 6-7 per 100, 000 persons but each type has a different prevalence and incidence. 85-90% of OI type one cases are caused by mutations in COL1A1/A2 (Martin and Shapiro, 2007). OI occurs equally in males, females and all ethnic groups. The prevalence and incidence of OI types 1-3 in Australian populations can be seen in Table 1 below.

Table 1. Prevalence and incidence of OI types I, II and II. Adopted from Van Dijk et al, (2011). -------------------------------------------------
Osteogenesis ImperfectaGene/locusLocation Chrm*Prevalence+Incidence++ -------------------------------------------------
Type 1 (I) COL1A1 17q21.333-4/100,0001-2/100,000
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Type 2 (II) COL1A1 17q21.331-2/100,000
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COL1A2 7q21.3
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Type 3 (III) COL1A1 17q21.331-2/100,0001.6/100,000 -------------------------------------------------
COL1A2 7q21.3
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Footnotes
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* Location of the gene on the chromosome
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+ Prevalence is the proportion of the population that has Osteogenesis Imperfecta/100,000 persons -------------------------------------------------
++ Incidence is the risk of developing Osteogenesis Imperfecta in specific time period/100,000 persons -------------------------------------------------
No prevalence due to early lethality of disease

Mutation in the COL1A1 and COL1A2 gene
Osteogenesis Imperfecta types I to IV are caused by an autosomal dominant mutations in both COL1A1 and COL1A2 (respectively on chromosome 17q21.33 and chromosome 7q21.3). Mutations destabilise mRNA and induce premature termination codons. Missense and frameshift mutations on these gene show association with a defected allele linked to the phenotype. Biosynthesis of collagen type I is essential to maintain the structure and integrity of the bone. Procollagen type I has three polypeptide chains, two pro-alpha1 chains (encoded by the COL1A1 gene) and one pro-alpha2 chain (encoded by the COL1A2 gene). Mutations of these chains cause the different types of OI. It was first thought that because there are two alpha-1 chains, a COL1A1 mutation may not affect collagen function compared to a mutation in COL1A2. Both chains are made from a sequence of amino acids, repeating Gly-X-Y-Gly-X-Y-//-Gly-X-Y-Gly-X-Y (Marini et al, 2006). Glycine is involved in helix folding. It is glycine substitutions which causes collagen to lose its triple helix structure. Sequence analysis of the COL1A1 promoter was used to determine if an association between mutations and regulatory sequences were responsible for low levels of expression. No substitutions were identified in promoter regions.

Mutation in the CRTAP and LEPRE1 gene
Osteogenesis Imperfecta type VII is caused by an autosomal recessive mutation in the CRTAP gene on chromosome 3p22.3 encoding a cartilage-associated protein. OI type VIII is also an autosomal recessive disorder caused by a mutation in the LEPRE1...
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