Fragile X Syndrome

Instructor:

Muhammad Imran Shabbir, PhD

Lecture

www.fragilex.org.uk/ page6.htm

Signs and Symptoms

• Mild to Moderate Mental Retardation

• Long, narrow face• Large, protuberant ears• Macroorchidism (enlarged

testicles)• behavioral characteristics

such as stereotypic movements (e.g. hand-flapping), and social anxiety.

• Hypotonia (low muscle tone)

Sign and Symptoms (Detailed)

Background

• X-linked disease• Mutation is located at Xq27.3• FMR1 Gene– Polymorphic (CCG)n repeat in

the 5’ untranslated reagion of exon 1

– Hypermethylation of a CpG island upstream of the mutation

Molecular Basis• In 1991, scientists discovered the gene (called FMR1) that causes Fragile X. In

individuals with Fragile X Syndrome, a defect in FMR1 (a full mutation) shuts the gene down. Like a defective factory, the FMR1 gene cannot manufacture the protein that it normally makes.

• Some indiviuals are carriers: they have a small defect in the FMR1 gene (called a premutation) but do not show symptoms of Fragile X.

• Fragile X is inherited. Carrier men (transmitting males) pass the premutation to all their daughters but none of their sons. Each child of a carrier woman has a 50% chance of inheriting the gene. The fragile X premutation can be passed silently down through generations in a family before a child is affected by the syndrome. A DNA blood test identifies both carriers and affected individuals. While the exact prevelance of Fragile X is unknown, recent studies indicate the statistics below:

• 1 in 2000 boys and 1 in 4000 girls are estimated to be affected

Molecular Basis• Named for its association with a chromosomal fragile site observed in many

patients (FRAXA chromosomal locus Xq27.3), fragile X syndrome (FXS) is the most common cause of inherited mental retardation (MR).

• FXS results from loss or severe reduction of the protein FMRP, encoded by the FMR1 (fragile X mental retardation) gene.

• All patients with FXS have mutations in FMR1, as no mutations leading to FXS have been identified in other genes.

• Both males and females may be affected with FXS, but females are typically less severely affected. Thus, FXS is considered to be X-linked dominant with reduced penetrance in females.

• The molecular genetics of FMR1 are complex. A repeated trinucleotide sequence, composed primarily of CGG repeats, is located in the untranslated portion of exon 1, ending 69 base pairs upstream of the translational start.

Molecular Basis• Nearly all mutations (>99%) resulting in FXS occur as instability of the

trinucleotide repeat,leading to dramatic expansion of the repeat segment (>200 to a few thousand repeats) accompanied by aberrant hypermethylation of CpG dinucleotides within the gene (full mutations).

• Relatively rare deletions and point mutations in FMR1 account for the remaining mutations found in patients with FXS.

• The mechanism of repeat instability in FMR1 is believed to be DNA polymerase slippage during DNA replication.

• AGG repeats, spaced at about 10 repeat intervals within the CGG repeat segment, may mitigate potential repeat instability through disruption of higher-order molecular structures formed during DNA replication.

• These secondary structures contribute to polymerase slippage, and alleles that lack interrupting AGG repeats are at higher risk for expansion.

Anticipation

Stuttering Alleles• Some genetically inherited

diseases have more severe symptoms each succeeding generation due to segments of the defective genes being doubled in their transmission to children (as illustrated below). These are referred to as stuttering alleles or unstable alleles. Examples of this phenomenon are Huntington's disease, fragile-X syndrome, and the myotonic form of muscular dystrophy.

Unstable allele doubling each generation

FMR1—Tripple Repeat Expansion