John Hay
John Hay Biomedical
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Rough draft.This research track is under review with Dr. Atit's lab. Content and sequence may still change.
The Baby Mateo Case
Genetics domainMedical Interventions (MI), with PBS overlapLesson 8 of 20Your seat: Variant analyst

One Gene, Two Diseases

Discovery question

Why does one gene cause two different diseases?

💡 The mechanism of a typo, not just the gene, predicts severity: a full-length that interferes () is worse than a missing one ().

The plan

Prerequisite check

Before this page, you should know
  • DNA is read three letters at a time as codons; the run of codons is the .
  • A change swaps one amino acid; the stays full length but may be altered.
Today's new idea is only
The mechanism of a typo, not just the gene, predicts severity: a full-length that interferes () is worse than a missing one ().
Learn first

What you will learn

Goal: Students will connect mechanism to phenotype, contrasting (truncating, milder Van der Woude) with action (DNA-binding-domain , more severe popliteal pterygium).

Know by the end
  • IRF6 has a (residues 7 to 115) and a ; changes are enriched in the DNA-binding domain but not the protein-binding domain.
  • Truncating typos (/) spread across the gene cause through (half-dose).
  • DNA-binding-domain changes cause more severe popliteal pterygium syndrome by acting , where the faulty interferes with the good copy.
  • About 67% of PPS families carry the R84C or R84H hotspot in the , and the rule is strong but not absolute.
Learn first

Model: Where the typos land, and two ways to break a two-copy machine

The IRF6 has two main parts: a (residues 7 to 115) that grabs DNA and a that links to partner proteins (UniProt O14896). Researchers mapped variants from 549 families and recorded both the typo type and the disease. Truncating typos (/, e.g. R250X) spread across the whole gene cause the milder (, lip/). in the DNA-binding domain (e.g. R84C, R84H) cause the more severe popliteal pterygium syndrome (cleft plus skin webbing, genital and limb anomalies). Reported numbers: missense changes are significantly enriched in the DNA-binding domain (p around 0.0001) but not the protein-binding domain; truncating changes are spread evenly; about 67% of PPS families carry R84C or R84H.

You have two copies of IRF6, one from each parent; picture each as a worker carrying a load. Scenario A (one worker quits): a truncating typo makes one copy produce no usable , so one working copy does the job of two; if that is not enough, the job falls short (running on half-dose). Scenario B (one worker sabotages): a DNA-binding-domain makes one copy produce a full-length but broken protein that jams the good copy when they pair up to grab DNA, so function drops below half (poisoning the team). Kondo and colleagues proposed exactly this: VWS is consistent with simple , while severe PPS is consistent with a protein that actively interferes.

Read this in pieces, one chunk at a time
Do the work

Explore (work the model before reading on)

  1. Which typo type clusters in the , and which disease does it cause?
  2. Which disease is more severe, and what extra features does it add beyond clefting?
  3. In which scenario does the bad copy interfere with the good copy?
  4. Truncating typos cause the milder disease and DNA-binding-domain cause the severe one. Why would a full-length-but-broken be MORE damaging than no protein at all from that copy?
  5. About 67% of PPS families carry a change at residue 84 in the . Connect that location to the sabotage scenario: why does the part that grabs DNA matter so much?
  6. Some R84C families have mild disease and some truncating changes cause severe disease. Predict one reason the same typo might not always give the same outcome.
  7. In one sentence, what pattern links the MECHANISM of a typo to the SEVERITY of the disease?
The plan

Guided notes

1

Haploinsufficiency

Model start: means one working copy is not enough; truncating typos cause milder this way.
  • One copy makes no usable , so you run on ____ dose, and one working copy is not enough for normal development.
  • This is the mechanism behind milder , caused mostly by ____ typos (, ) spread across the gene.
2

Dominant-negative

  • One copy makes a full-length but broken that also ____ with the good copy, dropping function below half.
  • This is the mechanism behind more severe popliteal pterygium syndrome, caused by ____ typos concentrated in the ____ domain, especially the R84 hotspot.
3

Why location matters

  • IRF6 proteins pair up to grab DNA; a in the DNA-____ domain lets the broken still pair but ruins the grip, so the pair fails.
  • This is strong but not absolute, so geneticists pair it with family history.
Explore

Reading the Research

What to read
Read the title and the abstract only, not the whole paper. Kondo S, et al. 2002. IRF6 mutations cause VWS and PPS. Nat Genet. [PMID:12219090]
Why this source matters
This is the published evidence behind today's idea: The mechanism of a typo, not just the gene, predicts severity: a full-length that interferes () is worse than a missing one ().
Words to unlock first
haploinsufficiencydominant-negativeDNA-binding domainloss of functiongenotype-phenotype correlation
Reading moves
  1. Skim the title and abstract first to get the gist.
  2. Circle the one sentence that states the main claim.
  3. Box the evidence the authors give for that claim.
  4. Mark one sentence that confuses you, and move on.
Stop point
You do not need the methods or statistics yet. If a sentence is about lab technique or math you have not learned, mark it and skip it.
Your output
Write one claim-evidence sentence: what this source claims, and the one piece of evidence that backs it up.
Lab day

Using the database (what to capture)

Part of today's expected outcome is to actually open the tool below and write down the value it gives you. That captured value is the evidence you will use in your Claim, Evidence, Reasoning. Follow the steps, use the labeled screenshot so you do not get lost, and record each field.

UniProt
Open the tool

The reference record for a : its length, its domains, and what each part does.

When you use this: Use this when you need to know which PART of the a variant hits, so you can predict whether it breaks a working region.
What the screen looks like
uniprot.org/uniprotkb/O14896 IRF6 human 1 Protein entry: IRF6 2 Length + domains 467 aa · DNA-binding + SMIR domains 3 1 Open the IRF6 entry (O14896). 2 Go to the Family & Domains section. 3 Read the length and which domains exist.
A labeled map of the screen. The circled numbers match the steps.
Step by step
  1. 1Open uniprot.org and search IRF6 human, then open entry O14896.
  2. 2Scroll to the Family and Domains section.
  3. 3Read the length and which domains exist (for example the ).
Capture these fields
  • Accession (the protein's ID): O14896
  • Length (amino acids): 467 aa
  • Domains / regions: A DNA-binding domain and a protein-partner (SMIR) domain
How to read it: The domains tell you which part of the does which job. A variant that lands inside the is more likely to break IRF6's -factor function than one in a spacer region.
Lost? UniProt help: reading protein domains
OMIM
Open the tool

Catalogs genes and the inherited diseases they cause, with a stable number per entry. It is a professional database; use MedlinePlus Genetics as the student-friendly fallback if access stalls.

When you use this: Use this when you have a gene and want the full list of named diseases it causes and how they are inherited.
What the screen looks like
omim.org/entry/607199 IRF6 1 Gene entry: IRF6 (#607199) 2 Diseases linked to this gene VWS #119300 · PPS #119500 3 1 Open the IRF6 gene entry. 2 Scroll to the phenotype table. 3 Read the diseases and inheritance.
A labeled map of the screen. The circled numbers match the steps.
Step by step
  1. 1Open omim.org and search IRF6, then open the gene entry (#607199).
  2. 2Scroll to the phenotype (disease) table.
  3. 3Read the diseases linked to the gene and the inheritance pattern.
Capture these fields
  • Gene entry (MIM number): IRF6, #607199
  • Disease(s) it causes: Van der Woude syndrome (#119300); popliteal pterygium syndrome (#119500)
  • Inheritance: Autosomal dominant
How to read it: One gene can map to more than one named disease. OMIM ties the gene to its conditions and inheritance pattern, so you know what to expect in a family.
Lost? About OMIM (professional database; use MedlinePlus fallback if blocked)
MedlinePlus
Open the tool

Plain-language explanations of a gene or condition, written for patients and families.

When you use this: Use this when a research paper is too dense, or when you need to explain a finding to Mateo's family in everyday words.
What the screen looks like
medlineplus.gov/genetics IRF6 gene 1 Plain-language gene page 2 What the gene does + linked conditions Helps the face join · cleft, VWS 3 1 Search the gene or condition. 2 Read the summary in everyday words. 3 Note the conditions it links to.
A labeled map of the screen. The circled numbers match the steps.
Step by step
  1. 1Open medlineplus.gov/genetics and search the gene or condition (IRF6).
  2. 2Read the summary written in everyday words.
  3. 3Note the conditions the gene is linked to at the bottom of the page.
Capture these fields
  • Topic: IRF6 gene
  • Plain-language summary: IRF6 helps the tissues of the face join correctly before birth.
  • Linked conditions: Van der Woude syndrome; nonsyndromic cleft
How to read it: Start here when a research paper is too dense. MedlinePlus gives you the gist in everyday words so you can go back to the harder source knowing what it is about.
Lost? About MedlinePlus Genetics
Where this fits
Tested on (Ohio WebXam)
Genetics of Disease · 072130
PLTW lesson
MI · Genetics domain · Unit 2 How to Screen Your Genes, 2.1 Genetic Testing and Screening
WebXam domain
Bio-Molecular Technology
Evidence to produce
For two of Mateo's relatives' IRF6 results (R250X and R84C), name the likely mechanism (haploinsufficiency or dominant-negative) and the likely disease (milder VWS or more severe PPS), with one-sentence reasoning each.
Lab / skill
Medical Interventions (MI) · Principles of Biomedical Science (PBS)
Words

Vocabulary (the same words your classes use)

Explore

Vetted readings for this lesson

The plan

Track your progress today

Check these off as you work through the lesson, then submit. This tells Mr. Mendoza how you're doing so he can help the class. It does not replace turning in your producible.

Use the code Mr. Mendoza gave you, not your name. Saved on this device.

Check off as you finish
  • Read the Model and answered the Explore questions.
  • Filled in the guided notes in my own words.
  • Defined the new vocabulary with an example.
  • Opened UniProt and OMIM and MedlinePlus and recorded the value it gave me.
  • Built the producible: For two of Mateo's relatives' IRF6 results (R250X and R84C), name the likely mechanism (haploinsufficiency or dominant-negative) and the likely disease (milder VWS or more severe PPS), with one-sentence reasoning each.
  • Wrote my Claim, Evidence, and Reasoning exit ticket.
Pick your period and code first.
See the grading rubric
See an example of today's finished work, and a WebXam practice questionA worked model of the producible plus one exam-style item with the answer and full rationale.
Check yourself

Exit ticket (Claim, Evidence, Reasoning)

  • Claim: A DNA-binding-domain in IRF6 tends to cause ____ disease than a truncating change.
  • Evidence: The data show changes are enriched in the and ~67% of the severe PPS families carry the ____ hotspot.
  • Reasoning: Therefore mechanism predicts severity, because a ____ while only ____.
How this is graded (rubric)
For: For two of Mateo's relatives' IRF6 results (R250X and R84C), name the likely mechanism (haploinsufficiency or dominant-negative) and the likely disease (milder VWS or more severe PPS), with one-sentence reasoning each.
CriterionProficientDevelopingBeginning
CompleteEvery required part of the artifact is present and filled in.Most parts are present, but one is missing or left blank.Several parts are missing.
AccurateThe science and data are correct and match the evidence.Mostly correct, with a small factual slip.Key science or data is wrong.
Scientific reasoning (CER)States a claim, backs it with specific evidence, and explains the reasoning.Has a claim and evidence, but the reasoning is thin or missing.Gives an answer with no evidence or reasoning.
Professional communicationClear, organized, and labeled the way a clinician or scientist would write it.Readable but disorganized or missing labels.Hard to follow.
SubmittedTurned in the right way (Schoology for routine work) and confirmed.Turned in, but in the wrong place or unconfirmed.Not turned in.
How the model answer scores against this rubric
  • CompleteProficient: Nothing is left blank: the model fills every part of "For two of Mateo's relatives' IRF6 results (R250X and R84C), name the likely mechanism (haploinsufficiency or dominant-negative) and the likely disease (milder VWS or more severe PPS), with one-sentence reasoning each.".
  • AccurateProficient: Every number and claim matches the case evidence.
  • Scientific reasoning (CER)Proficient: It names a claim, cites the specific evidence, and explains the reasoning, not just the answer.
  • Professional communicationProficient: It is organized and labeled like a real chart note.
  • SubmittedProficient: It would be turned in on Schoology and confirmed.
Explore

Where this leads: careers

Variant analyst Clinical geneticist Protein scientist

What's next: The harmful IRF6 changes we studied are rare and cause syndromes. Most clefts are isolated and common. Where is the common, hidden variant, and why have we not seen it in the code?

Kinds of Typos in DNAThe Hidden Regulatory Variant
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