A study published online in the May 3 edition of Developmental Cell reveals that researchers at the Weill Cornell Medical College and the Rockefeller University have identified the first gene, called Nkx2.5, which is associated with a rare condition called congenital asplenia, in which babies are born without a spleen.

Not having a spleen means that these children have a high mortality risk due to infections they are unable to defend themselves against.

The study, a collaboration between Dr. Selleri and her team, and Dr. Jean-Laurent Casanova at the Rockefeller University, who is professor in the St. Giles Laboratory of Human Genetics of Infectious Diseases demonstrated that Nkx2.5 regulates genesis of the spleen during early development in mice.

The discovery looks promising for developing a simple genetic screening test for Nkx2.5 mutations, which could alert expecting parents that their developing child may be developing without a spleen. A diagnostic scan would be able to confirm the finding.

Leading researcher, Dr. Licia Selleri, an associate professor in the Department of Cell and Developmental Biology at Weill Cornell Medical College, explains:

“The great news is that with the appropriate preventive antibiotic treatment these children will not succumb to fatal infections. This test could potentially save lives.”

Given that t he spleen is partly responsible for fighting infections, means that children without a spleen require life-long treatment with antibiotics.

The majority of congenital asplenia is diagnosed during an autopsy after a child’s sudden and unexpected death from a rapidly lethal infection by bacteria that causes pneumonia or meningitis.

Dr. Selleri states:

“For those reasons, we believe this condition is not quite as rare as believed. Not every child who dies from an infection is given an autopsy.”

Patients with congenital asplenia do not usually lack other organs. However, they do sometimes have abnormalities of the heart and blood vessels. Most of these incidents are sporadical and therefore not thought to be inherited. Isolated Congenital Asplenia (ICA) is the absence of a spleen with no other developmental abnormalities. Although scientists hypothesized that the cause of ICA is genetic, they did not discover any candidate genes in humans prior to this study.

Dr. Casanova was leading researcher in an earlier study of 20 ICA patients that showed that most children suffered their first serious infection by the time they were one year old, with nine children dying of an invasive pneumonia, whilst Dr. Selleri has a long history of studying congenital asplenia in mice. He discovered that the transcription factor Pbx is the prime regulator of spleen development in mouse models.

Dr. Matthew Koss, a recent Ph.D. graduate, created a strain of mice with no Pbx in the spleen, and some that were born without a spleen. Koss discovered a regulatory module, which is controlled by Pbx and targets Nkx2.5 (a gene downstream of Pbx) in the developing spleen of the mouse embryo and that Pbx controls the spleen’s growth by directly regulating Nkx2.5 expression, which in turn controls cell proliferation within the primitive spleen organ.

The team sequenced genetic samples from ICA patients, which they then analyzed by using whole exome sequencing technology, which allows sequencing of the entire coding genome of multiple patients. They found Nkx2.5 to be mutated in a family of asplenic patients, some of which died from lethal infections, which confirms that Nkx2.5 is significant in human congenital asplenia in the same way as it is in the mouse model.

Dr. Selleri declares:

“This study illustrates the unique strength in using mouse models and human genetics hand-in-hand. It demonstrates how genetic pathways identified in mouse models can be exploited to further understand the pathogenesis of human disease towards a better prenatal diagnosis.”

To develop a comprehensive prenatal test, Dr. Selleri states that further studies need to be conducted in other patients and families with congenital asplenia.

She concludes:

“It may be that there are other mutations that are acting in concert or independently of Nkx2.5 in other asplenic patients.”

The Rockefeller University lab is currently conducting further studies in human patients, whilst additional studies on mouse models are continuing at the Weill Cornell lab.

Written By Petra Rattue