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Cause of rare growth disease discovered

bjb42 — Sun, 24 Jun 2012 18:00:54 +0000

A rare genetic disease which causes some parts of the body to grow excessively has been linked to a cancer-associated mutation that drives cell growth, potentially paving the way for new treatments. ̽��ֱ��research findings were published today, 24 June, in Nature Genetics.

An international collaboration among the ̽��ֱ�� of Cambridge, the Sanger Institute, and the Babraham Institute in the UK and the National Institute for Health in the US has discovered that unrestrained and sometimes massive fatty ‘overgrowth’ affecting only some body regions is caused by mutations in the phosphatidylinositol-3-kinase (PI3K)/AKT signalling pathway (which is critical for cellular growth and metabolism).

̽��ֱ��types of mutations which cause these overgrowths typically arise during embryonic development. Unlike conditions caused by genetic mutations which are transmitted from parents (in which every cell in the body is affected), in this condition only the ‘offspring’ of the cell where the mutation occurs carry the change. This accounts for why only some parts of the body are affected.

̽��ֱ��scientists from the ̽��ֱ�� of Cambridge and the Sanger Institute, who were funded mainly by the Wellcome Trust, first studied a patient who had severe overgrowth of her legs but a normal upper body. By conducting a genetic analysis of cells sampled from the affected and unaffected areas, they were able to identify a critical mutation which caused the overgrowth in her legs. Scientists at the Babraham Institute then made use of their unique lipidomics mass spectrometry capability to demonstrate abnormal activation of the signalling pathway in cells from the leg but not the arm. These studies were extended in collaboration with scientists at the US National Institute for Health in Maryland, leading to discovery of nine other patients with similar mutations, confirming the results and suggesting that activation of the PI3K pathway may be a common cause of this form of fatty overgrowth.

Dr Robert Semple, from the ̽��ֱ�� of Cambridge Metabolic Research Laboratories at the Institute of Metabolic Science, said: “ ̽��ֱ��mutations we have found are well known as ‘cancer mutations’. However, in cancers they are found with numerous other genetic changes, while here they are apparently in isolation.”

“Studying our patients will thus give new information about the specific role played by these mutations in cancer. Moreover, the major effort to make drugs targeting these mutations for cancer therapy should benefit people with this rare problem, and when drugs safe enough for long-term use are developed they may offer for the first time a targeted, and effective, non-surgical treatment for the excessive growth. We are testing currently available drugs in cells at present.”

Dr Inȇs Barroso, from the Wellcome Trust Sanger Institute, said “We wanted to understand the biology behind this rare and debilitating disorder and thought exome sequencing - sequencing the region of the genome where genetic material is translated into proteins - would be a powerful approach to facilitate the discovery of the underlying mutation. Using DNA sequencing we found that a mutation associated with cancer in the gene PIK3CA was found only in the affected cells of patients”.

Professor Michael Wakelam from the Babraham Institute said “This study exemplifies the importance of collaboration between basic and clinical scientists in translating methodologies and concepts from the research lab to bring about greater understanding and potentially treatment of human disease.”

Scientists hopeful discovery will provide a biological target for drug therapy.

̽��ֱ��mutations we have found are well known as ‘cancer mutations’. However, in cancers they are found with numerous other genetic changes, while here they are apparently in isolation.

Robert Semple

Nature Genetics.

Example of fatty overgrowth, affecting specific body regions, caused by mutations in the phosphatidylinositol 3 kinase PI3K (AKT) signalling pahtway.

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Key to regulation of puberty discovered

bjb42 — Thu, 11 Dec 2008 00:00:00 +0000

̽��ֱ��research, published in this week's Nature Genetics, identified the hormone Neurokinin B as a critical part of the control system that switches on the master regulator of human puberty. Although Neurokinin B was previously known to be present in the hypothalamus, the part of the brain that controls puberty, its key role was not previously appreciated.

̽��ֱ��identification of Neurokinin B could lead to new treatments for sex hormone dependent diseases like prostate cancer, new approaches to contraception, and its manipulation could result in new treatments for children with delayed or abnormal puberty.

It has long been known that a specific hormonal signal from the hypothalamus is essential to switch on the system that controls the production of sex hormones from the ovaries and testis. Turning on the system is essential to enter puberty and maintain sexual function in adults.

Control over this system is governed by the brain through the release of the hormone GnRH (gonadotropin releasing hormone) which starts a series of processes that ultimately leads to the production of sex hormones. However, how GnRH secretion is turned off after birth, and how it reactivates at puberty, has been unclear.

In order to identify new signals involved in regulating this process, the researchers used a strategy of searching for genetic defects in families in Turkey in which more than one member did not go through puberty, making an inherited defect likely. They discovered mutation in two genes: TAC3 (one family) and TACR3 (three families).

Mutations in these genes severely affect the function of Neurokinin B. ̽��ֱ��TAC3 gene codes for Neurokinin B while TACR3 produces its receptor. These mutations were only found in members with the condition, severe congenital gonadotropin deficiency, and not their siblings. Affected individuals were all homozygous (they have two identical copies of the gene) for these mutations.

A small number of studies using mice and rats had previously linked Neurokinin B to puberty, but the wider view was that its main role was instead in water balance, cognitive function or a number of other processes. This research clears this uncertainty and establishes the central role for Neurokinin B and its receptor in puberty and the regulation of sexual and reproductive function.

Commenting on the research Dr Robert Semple, from the ̽��ֱ�� of Cambridge and one of the authors of the study said: "As a practicing doctor I am excited by this discovery because it immediately helps to understand the underlying problem in rare patients with inherited defects in sexual maturation, and suggests a potential target for their specific treatment. However identifying single genetic defects in patients with rare disorders also has implications for understanding normal regulation of key bodily functions, and is one of the most powerful ways of proving the genes concerned.

" ̽��ֱ��Neurokinin B/Neurokinin 3 receptor system is highly amenable in principle to targeting as a treatment, and I expect that this genetic discovery will lead to intense efforts to understand Neurokinin B's role in puberty in more detail, and to try to develop clinically valuable drugs."

Professor Steve O'Rahilly, from the ̽��ֱ�� of Cambridge said: "This unexpected finding puts one more important piece in the unfinished jigsaw puzzle that is our understanding of puberty. It could also open up new ways of treating certain sex hormone related diseases"

A team of scientists from the ̽��ֱ�� of Cambridge and the ̽��ֱ�� of Cukurova in Turkey has taken a major step to understanding how the brain controls the onset of puberty.

As a practicing doctor I am excited by this discovery because it immediately helps to understand the underlying problem in rare patients with inherited defects in sexual maturation, and suggests a potential target for their specific treatment.

Dr Robert Semple

Son of Groucho from Flickr

Discarded Teenagers

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