An international collaboration of scientists including researchers of the Institute of Human Genetics Göttingen have determined specific mutations in POLR3A as the genetic cause of Wiedemann-Rautenstrauch syndrome. This rare disorder is associated with signs of accelerated aging; it is thus a so called progeroid syndrome. Affected children show characteristic features like growth retardation, sparse scalp hair, lipodystrophy and an unusual face already at birth. They appear to be prematurely aged.

POLR3A, the protein encoded by the gene, forms the largest subunit of the RNA polymerase III complex. This enzyme is crucially involved in the synthesis of RNA in transcription. Specifically, RNA polymerase III transcribes small RNAs including ribosomal RNA (rRNA) and transfer RNA (tRNA). In their study recently published in the Journal of Medical Genetics, the researchers discovered biallelic POLR3A mutations in eight affected families. The types of the identified mutations suggest that specific combinations of compound heterozygous variants of POLR3A must be present to cause the phenotype, including one variant that has a strong detrimental effect on protein function (splice-site or truncating mutation) and a variant exerting a milder functional effect (often an intronic variant).

Progeroid syndromes are a clinically heterogeneous family of disorders which share the feature of premature aging. Various genetic defects have so far been identified as molecular causes, affecting fundamental processes like chromatin structure, genome stability, transcription control, DNA repair, nuclear structure and epigenetic regulation. Researchers at the UMG Institute of Human Genetics are intensively investigating this group of disorders. Their work within this study has been funded by CRC 1002 (“Modulatory units in heart failure”; speaker Prof. Dr. Gerd Hasenfuß). The Institute has also established a special clinic for families with progeroid syndromes.

Specific combinations of biallelic POLR3A variants cause Wiedemann-Rautenstrauch syndrome
Paolacci S, Li Y, Agolini E, Bellacchio E, Arboleda-Bustos CE, Carrero D, Bertola D, Al-Gazali L, Alders M, Altmüller J, Arboleda G, Beleggia F, Bruselles A, Ciolfi A, Gillessen-Kaesbach G, Krieg T, Mohammed S, Müller C, Novelli A, Ortega J, Sandoval A, Velasco G, Yigit G, Arboleda H, Lopez-Otin C, Wollnik B*, Tartaglia M*, Hennekam RC* (*contributed equally).
J Med Genet. 2018 Oct 15; Epub ahead of print