Hutchinson-Gilford Syndrome: Genetics

Since 1960 Hutchinson-Gilford Syndrome (HGS) has been suggested to be a genetic syndrome, but until 2003 debate continued on whether it was rare but dominant, or autosomal recessive. Unfortunately, due to the rarity of the disease and the fact that many cases were actually similar diseases misdiagnosed as HGS, relatively little is known about the pathophysiology of the disease. In 2003, Erikson et al. traced the disease to a locus on chromosome 1 responsible for coding the protein Lamin A. This protein is a significant and essential component of the nuclear laminae, a part of the nuclear envelope. The LMNA gene, which codes for Lamin A, has already been proven responsible for several other disorders, including mandibuloacral dysplasia, whose symptoms are often mistaken for HGS, but which does not share the shortened lifespan that typifies HGS patients.

Children with HGS showed a heterozygous C to T mutation at nucleotide 1824 of chromosome 1. Although this substitution does not have any effect on the amino acid translated from the sequence (glycerin 608), the mutation causes a truncated transcription of mRNA in cis, and in trans inhibits transcriptional processing of the normal allele, making it a dominant negative mutation. However, despite this finding and evidence that HGS is caused by a de novo (brand new) point mutation for every case, empirical evidence from a family which apparently has passed down the disease from two recessive parents keep debate open at this time as to whether the disease is actually dominant negetive or autosomal recessive.

The effect of this truncation is to strongly inhibit the production of Lamin A. On a larger level, this means cellular nuclei are altered in size and shape, often with holes that allow for chromatin leakage. Function of Lamin B1 is also disrupted, due to a loss of function to its nuclear localization proteins. The resulting weakness of the nucleus causes the ageing-like symptoms that characterize the disease.