美國(guó)費(fèi)城兒童醫(yī)院的研究人員確定出了引發(fā)Alagille 綜合癥的第二個(gè)基因,。Alagille綜合征又稱先天性肝內(nèi)膽管發(fā)育不良征，動(dòng)脈-肝臟發(fā)育不良綜合征,，是一種影響多種器官的遺傳發(fā)育疾病,。這些新發(fā)現(xiàn)將在了解腎臟疾病方面有更廣泛的意義。這種綜合癥的第一個(gè)相關(guān)基因也是該研究組確定出來(lái)的,。
研究人員發(fā)現(xiàn),，NOTCH2基因的突變與患者和家族中的腎臟異常有關(guān)。雖然,，Alagille綜合癥比較罕見(jiàn),，但是器官疾病卻不少見(jiàn)。這項(xiàng)研究的新發(fā)現(xiàn)表明,，這個(gè)生物途徑上的基因可能在腎臟疾病中具有更廣泛的作用,。這項(xiàng)研究的結(jié)果刊登在7月的American Journal of Human Genetics上。
Alagille綜合癥的發(fā)病機(jī)率約兩萬(wàn)分之一,，是一種復(fù)雜疾病,，通常會(huì)影響到肝臟、心臟,、眼睛,、臉部和骨骼。一些患者的癥狀很輕微,，但另外一些則很嚴(yán)重,、甚至出現(xiàn)威脅生命的心臟或肝臟缺陷。
研究人員已經(jīng)確定出JAG1和NOTCH2基因都參與了Notch信號(hào)通路,。JAG1編碼配基Jagged1——一種觸發(fā)這個(gè)通路中受體的信號(hào)蛋白,；NOTCH2基因編碼Notch2——是這些受體中的其中一個(gè)。這個(gè)通路在胚胎發(fā)育期間被活化,，并負(fù)責(zé)將信號(hào)傳遞給細(xì)胞,，從而促進(jìn)特定器官的發(fā)育。這些基因的突變被任務(wù)能夠干擾正常的發(fā)育,。配基和受體就好比鑰匙和鎖,，如果一方出現(xiàn)問(wèn)題都會(huì)影響到正常的生長(zhǎng)和發(fā)育。
雖然Spinner博士的研究組只是分析了11名攜帶JAG2突變的Alagille綜合癥患者,，并發(fā)現(xiàn)其中兩人出現(xiàn)了NOTCH2突變,。進(jìn)一步對(duì)患者的三個(gè)家族成員的分析發(fā)現(xiàn)，他們也發(fā)生了相同的突變,。而且,，所有五個(gè)個(gè)體都發(fā)生了腎臟疾病。
雖然這項(xiàng)研究調(diào)查的患者數(shù)目很小,，但是這項(xiàng)研究是首次報(bào)道NOTCH2基因突變會(huì)導(dǎo)致人類疾病,。
英文原文：
Gene discovery may shed light on kidney disease
Second gene found for Alagille syndrome may have broader role
In a finding that may have broader implications for understanding kidney disorders, genetics researchers at The Children's Hospital of Philadelphia have identified a second gene that gives rise to Alagille syndrome, a genetic developmental disease that affects multiple organs. The Children's Hospital team previously discovered the first gene associated with this disease.
The researchers found that mutations in the NOTCH2 gene were linked to kidney abnormalities in patients and families. "While Alagille syndrome is relatively rare, organ diseases are not rare, and our findings suggest that genes on this biological pathway may have a broader role in kidney disorders," said study leader Nancy B. Spinner, Ph.D., a geneticist at The Children's Hospital of Philadelphia.
The study appears in the July issue of the American Journal of Human Genetics.
Dr. Spinner led the Children's Hospital team that identified mutations in the JAG1 gene as a cause of Alagille syndrome in 1997. Like the NOTCH2 gene analyzed in the current study, JAG1 is part of a signaling pathway that governs important processes in early human development.
Alagille syndrome, estimated to occur in one in 20,000 individuals, is a complex disorder, primarily affecting the liver, heart, eyes, face and skeleton. Some patients with Alagille syndrome have very mild symptoms or isolated problems, while others may have severe, life-threatening heart or liver defects.
Both the JAG1 and the NOTCH2 genes participate in the Notch signaling pathway. JAG1 codes for the ligand Jagged1, a signaling protein that triggers receptors in the pathway. The NOTCH2 gene codes for Notch2, which is one of those receptors. The pathway as a whole is active during embryonic development, and transmits signals to cells to develop into specialized organs. Mutations in those genes are thought to disrupt normal development, by, for instance, causing the defective bile ducts found in the livers of many patients with Alagille syndrome.
"Ligands and receptors are like keys and locks," said Dr. Spinner. "If either one is defective, it may interfere with normal growth and development."
Dr. Spinner's team previously determined that 94 percent of patients diagnosed with Alagille syndrome had mutations in the JAG1 gene. In the current study, they analyzed 11 patients with Alagille syndrome who did not have the JAG1 mutation, and found that two of them had mutations in NOTCH2. Furthermore, the patients had three family members, all mildly affected, who also had the same mutation. All five individuals had kidney disease.
Because their study identified only two families with NOTCH2 mutations, said Dr. Spinner, it is not definitive in establishing that those mutations cause a distinct variety of Alagille syndrome. However, it is the first study to report that mutations in the NOTCH2 gene cause human disease. Dr. Spinner is planning further studies to better characterize the role of NOTCH2 mutations and the Notch signaling pathway in the wider population of patients with kidney disorders.
She also will investigate liver involvement in Alagille syndrome under the Rare Diseases Clinical Research Network, recently established by the National Institutes of Health. "Part of the rationale for this research network is that, collectively, relatively rare diseases added together constitute a significant portion of the population," said David A. Piccoli, M.D., chief of Gastroenterology and Nutrition at Children's Hospital and a co-author of the study. "Another rationale is that studying relatively rare diseases may offer insights into more common diseases and into health in general."
The National Institute for Diabetes and Digestive Diseases supported this study, as did the Fred and Suzanne Biesecker Center at The Children's Hospital of Philadelphia. Co-authors with Drs. Spinner and Piccoli, all from Children's Hospital and the University of Pennsylvania School of Medicine, were Ian Krantz, M.D.; Ryan McDaniell, Daniel M. Warthen, Pedro A. Sanchez-Lara and Athma Pai.
About The Children's Hospital of Philadelphia: The Children's Hospital of Philadelphia was founded in 1855 as the nation's first pediatric hospital. Through its long-standing commitment to providing exceptional patient care, training new generations of pediatric healthcare professionals and pioneering major research initiatives, Children's Hospital has fostered many discoveries that have benefited children worldwide. Its pediatric research program is among the largest in the country, ranking second in National Institutes of Health funding. In addition, its unique family-centered care and public service programs have brought the 430-bed hospital recognition as a leading advocate for children and adolescents.
