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Woodhouse-Sakati Syndrome

Woodhouse-Sakati syndrome (WSS), also called "hypogonadism, alopecia, diabetes mellitus, intellectual disability and extrapyramidal syndrome", is a rare autosomal recessive genetic, multisystem disorder. Current known characteristics of the disorder include developmental malformations throughout the body, hearing loss, intellectual disability, and deficiencies involving the endocrine system. Due to the rarity of WSS, the majority of patients have a relatively high level of relatedness, therefore the range of affected ethnic backgrounds is narrow.

Symptoms

WSS has a wide array of symptoms including hair loss, hypogonadism, diabetes mellitus, hearing loss, intellectual disability, dystonia, and hypothyroidism. However, these symptoms are not present in all cases of WSS. The severity and the specific combination of symptoms strongly relates to the ethnicity of the disease carrier, as the phenotype of WSS patients is inherited from previous disease carriers and certain symptoms are more prevalent in certain ethnic backgrounds.

Endocrine Disorders

In the majority of WSS cases, endocrine disorders are the main symptom, but vary in their mechanisms. Hypogonadism involves gonads losing their ability to secrete hormones, such as testosterone in males, and estrogen in females. The inability to secrete the required hormones causes side effects such as no oocyte reserve in women and a severely reduced sperm count in males due to a lack of production. Hypothyroidism relates to a decrease in the thyroid's ability to secrete its hormones, causing potential weight loss, tiredness, and intellectual disability during human development, although symptoms may not be noticed until later in life and often go unnoticed. In some cases, hypothyroidism can be caused by gonadal disorders, including hypogonadism.

Genetics of WSS

Mutations in the C2ORF37 gene, located on human chromosome 2 at the locus 2q22.3-q35, are believed to be the cause of Woodhouse-Sakati syndrome. The mutated allele is very rare in the human population, and is inherited in a recessive manner from one generation to the next. Due to the rarity of the mutated allele, most cases of WSS are found in populations with high consanguinity, meaning there is a high degree of relatedness within the population where the disorder is found. The most common mutation to this region is a single base-pair deletion causing a frameshift of the open reading frame (ORF) in the C2ORF37 gene. In addition, variability of symptoms are also related to alternative splicing, with mutations to numerous exon donor and receiver splice sites altering the quality and quantity of the gene product. The varying effects of the mutation get passed on to the next generation, meaning that each different WSS-affected family will carry different underlying genetic causes and symptoms.

C2ORF37

The C2ORF37 gene, which contains 14 exons, encodes a protein with ubiquitous nucleolar expression. Found in multiple species, the nucleotide sequence of this gene is highly conserved, demonstrating its importance. Orthologs of the gene are also found in a number of species such as mice, rats, cows and chimpanzees. Although not yet completely understood, mutations to this gene, and thus alterations to its protein product, impact transcription in patient lymphoblasts. Low doses of the protein selectively blocks the nucleolar RNA polymerase, decreasing transcription, while high doses of the protein completely halts all transcriptional activity in the affected cell.