HNRNPH2 mutations have been detected in patients and are considered pathogenic, or disease causing . Heterogeneous Nuclear Ribonucleoprotein H2, or the abbrieviation HNRNPH2, is a gene, found on the X chromosome of an individual.

Chromosomes

A chromosome is a strand of DNA that is encoded with genes. Humans have 22 pairs of these chromosomes plus the two sex chromosomes (XX in females and XY in males) for a total of 46. Our daughters’ mutations have been found on just one of the two X chromosomes that they possess.

 How did the mutation occur?

The HNRNPH2 mutations have all been identified as de novo. This means neither the mother or the father of the person with the mutation is carrying the damaged gene. In other words, this is not something that was inherited by a parent. Instead, it is believed to have happened spontaneously at conception of the child.

 What about the other healthy, properly functioning X chromosome?

X-inactivation (also called lyonization) is a process by which one of the copies of the X chromosome present in female is inactivated. So when a cell is created, a random selection process takes place to “turn on” just one X chromosome (the cell doesn’t need 2 to survive- just one). The other is left “silent”. Since the selection is random, it is assumed that about HALF of our daughters’ cells have activated the mutated X chromosome. The other half, have activated the healthy X chromosome. It can be surmised that about half of the cells in our daughters’ bodies ARE getting their jobs done, while the remaining half are struggling to do so.

 What exactly has happened on the HNRNPH2 gene of our daughters?

DNA on a gene is a chain of amino acids that have been likened to a recipe card. Certain ingredients are needed for the expected result. Similarly, on our genetic codes, certain amino acids are expected to be present for normal/expected development to occur. Each of our daughters have been identified as having a “mis-write” or an improper ingredient on a particular location on the HNRNPH2 gene. There is an unexpected “change” or “variation” in a sequence of amino acids that normally stays the same, across people and other organisms that are known to have an HNRNPH2 gene.

What is the particular location on the gene with the mis-write, and is that location critical?

The area on the HNRNPH2 gene called nuclear localization sequence, or the NLS, is the area where our daughters’ mutations have been identified. This is a very important area of a gene.

 What is the NLS? Why is it important?

A nuclear localization sequence (NLS) is an amino acid sequence (an area of amino acids) that has the important job of ‘tagging’ proteins made by a cell for import into the cell nucleus by nuclear transport.

During a family meeting held at Columbia University in January of 2017, Drs. Chung and Bain explained that the NLS is an important area on a gene and likened it to a delivery center. Proteins made in the cytoplasm of a cell normally get tagged by the NLS to grant them entrance into the nucleus of the cell. The mutation or mis-spelling of an amino acid in the NLS, which our girls are identified as having, is most likely disrupting the tagging process, therefore important “deliveries” of proteins to the nucleus are NOT being made.

This creates two possible problems:

  1. Proteins that need to be brought into the nucleus of a cell are not getting delivered (begging the question “what exactly happens as a result of that?”)
  2. The proteins being created in the cytoplasm that are NOT being given entrance to the nucleus because of the mutation at the NLS, are left within the cytoplasm, hanging around, clogging up the cell (begging the question “what happens as a result of such clogging in the cytoplasm?”)

 

…. and so our quest to learn more and then find interventions to help these girls with the difficulties they face, and an ultimate cure, begins…. join us.