Author: Letizia Spidalieri
Date: 16/10/2013


Wolf-Hirschhorn Syndrome (WHS) is a multiple congenital anomalies/mental retardation syndrome, firstly described in 1961 by Cooper and Hirschhorn. Its frequency is estimated as 1/50000-1/20000 births, with a female predilection of 2:1. The disorder is caused by partial loss of material from the distal portion of the short arm of chromosome 4 (4p16.3).
Several Wolf-Hirschhorn syndrome patients have been studied but the molecolar basis of the syndrome remains poorly understood.
No single gene deletions or intragenic mutations have been shown to confer the full WHS phenotype. The pathogenesis of WHS is multigenic and variable expressivity and incomplete penetrance might play a role in WHS.
The diagnosis is suggested by the characteristic facial appearance, growth delay, psychomotor retardation and seizures (or EEG anomalies) and is confirmed by detection of a hemizygous deletion of the short arm of chromosome 4, called the Wolf-Hirschhorn syndrome critical region (WHSCR). The deletion proximal breakpoint varies from 4p15.32 to 4p16.3 and is terminal and includes both WHSCR.
The majority of individuals have a deletion with no other cytogenetic abnormality (a so called 'pure deletion'); the remaining have a more complicated cytogenetic finding such as ring 4 chromosome, 4p- mosaicism or a un unbalanced translocation leading to both a 4p monosomy and a partial trisomy for another chromosome arm.
Clinically, three different categories of the WHS phenotype are defined, generally correlating with the extent of the 4p deletion:
Small deletion (not exceeding 3.5 Mb) usually associated with a mild phenotype, lacking major malformations.
Large deletion (averaging between 5 and 18 Mb), the more frequent category, causes the widely recognizable WHS phenotype.
Very large deletion (exceeding 22-25 Mb) causes a severe phenotype that can hardly be defined as typical WHS.

The MMSET gene (also known as WHSC1) is located in the WHS critical region, WHSC, and its loss is considered to be responsable for the 'core' phenotypes of this disease (typical facies appearance, mental retardation, growth delay and seizures or EEG anomalies).

MMSET gene

Official symbol: WHSC1

Official full name: Wolf-Hirschhorn syndrome candidate 1

Also known as: WHS, NSD2, TRX5, REIIBP.

Location: 4p16.3

Gene type: protein coding

Summary: this gene encodes a protein that conteins four domains present in other developmental proteins: a PWWP domain, an HMG box, a SET domain and a PHD-type zinc finger. It is expressed ubiquitously in early development.

The WHSC1 gene has been identified, in a genetic screen for genes, involved in responding to replication stress, linking WHS to the DNA damage response (DDR). The WHSC1 protein is a member of the DDR pathway. WHSC1 localizes to sites of DNA damage and replication stress and is required for resistance to many DNA-damaging and replication stress-inducing agents.
Histone modifications contribute to the precise regulation of transcription by recruiting non-histone proteins and controlling chromatin conformation. Haploinsufficiency for some histone methyltransferases, are associated with Wolf-Hirschhorn syndrome.
WHSC1 gene, throught its SET domain, regulates the methylation status of the histone H4 K20 residue and is required for the recruitment of 53BP1 to sites of DNA damage.
53BP1 (p53-binding protein 1) is known to be an important mediator of the DNA damage response, with dimethylation of histone H4 lysine 20 critical to the recruitment of 53BP1 to double-strand breaks (DSBs). Although it is not clear how 53BP1 is specifically targeted to the sites of DNA damage, it has been proposed that H4K20 methylation increases locally upon the induction of double-strand breaks and that methylation of H4K20 at DSBs is mediated by the histone methyltransferase MMSET in mammals. Thus, it has been proposed that a pathway involving MMSET regulates the induction of H4K20 methylation on histone around DSBs, which in turn, facilitates 52BP1 recruitment.
Downregulation of MMSET significantly decreases H4K20 methylation at DSBs and the subsequent accumulation of 53BP1.

Finally, it has been supposed that Wolf-Hirschhorn Syndrome results from a defect in the DNA damage response.


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