Go to the OMIM website (https://www.ncbi.nlm.nih.gov/omim) and type 'dyskeratosis congenita autosomal dominant 1' (DKCA1) into the search bar. The result will include a clickable link to the disorder that has an OMIM number of 127550. Review the OMIM information you retrieve and notice that this disorder is caused by a mutation of a telomerase gene that results in abnormally rapid shortening of telomeres and the appearance of disease symptoms at progressively younger ages in successive generations of the affected families. Use this and other information on OMIM to assist with this problem. Go the reference number 15 at the bottom of the OMIM page for a link to a 2004 paper by Tom Vulliamy and colleagues that appeared in the journal Nature Genetics. Click on the 'Full text' option and download a copy of the paper. Look at Table 1 of the paper on page 448. This table lists the lengths of telomeres measured in members of the families in this study. Telomeres shorten with age, and the telomere lengths in Table 1 are age-adjusted. The negative numbers for telomere lengths in the table indicate that telomeres are shorter than average for age, and the more negative the number, the shorter the telomere. Based on Table 1, discussion in the Vulliamy et al. (2004) paper, and information available on OMIM answer the following: Why are telomeres of people with DKCA1 shorter than average?

Key Concepts

Telomeres

Telomeres are repetitive nucleotide sequences located at the ends of chromosomes, serving to protect them from deterioration or fusion with neighboring chromosomes. They shorten with each cell division, which is a normal part of aging. In conditions like dyskeratosis congenita, mutations in telomerase can lead to accelerated telomere shortening, resulting in premature aging and associated health issues.

Telomerase

Telomerase is an enzyme that adds nucleotide sequences to the ends of telomeres, counteracting their natural shortening during cell division. In individuals with dyskeratosis congenita autosomal dominant 1 (DKCA1), mutations in the telomerase gene impair its function, leading to insufficient telomere maintenance. This results in shorter telomeres and contributes to the early onset of disease symptoms.

Genetic Inheritance and Penetrance

Genetic inheritance refers to how traits and disorders are passed from parents to offspring, while penetrance describes the proportion of individuals with a specific genotype that express the associated phenotype. In DKCA1, the disorder exhibits a pattern of anticipation, where symptoms appear at younger ages in successive generations, indicating a high penetrance of the telomerase mutation and its impact on telomere length.