Resulting Condition: Hutchinson-Gilford Progeria

by Richard Mitchell, MD, PhD

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    00:00 All right, so an example of a disease having to do with a nuclear membrane.

    00:04 This is a tragic disease. It is not a public health menace.

    00:07 This is one that is extremely rare, but it's a very illustrative disease.

    00:11 And this is called Hutchinson-Gilford progeria.

    00:14 So, progeria is a number of syndromes, and Hutchinson-Gilford just happens to be one of them, but a number of syndromes that lead to premature aging.

    00:23 The little kid that -- the little kid in front of you has a body that's essentially like a 50 or 60-year-old body in terms of its atherosclerotic burden in terms of the kind of aging and senescence of a number of the tissues including the skin.

    00:38 So, they lose their hair. They have a very abnormal joint structure.

    00:43 They lose a lot of adipose tissue. So, it's premature aging that happens.

    00:48 And it happens because of a mutation of a protein that is part of the normal nuclear membrane.

    00:55 So, lamin A is a protein that normally is synthesized and then modified, so that it can insert into the membrane via a farnesyl linkage.

    01:05 Farnesyl is just a lipid linkage.

    01:08 And so, it's one of the other ways that proteins can associate with a membrane.

    01:11 Normally, in you and I, because we don't have Hutchinson-Gilford progeria, in us, our protein is such that we can cleave that farnesyl linkage.

    01:25 The protein doesn't have a mutation.

    01:26 In these kids, they can't cleave it, so that lamin A stays stuck to the membrane forever and ever.

    01:34 And that lamin A anchors additional proteins.

    01:37 So, you can see in the upper right-hand side in the circles are the lamin A nuclear complexes stuck in the nuclear membrane, and they're associated with a lot of the other purple bars which represent nuclear cytoskeletal elements.

    01:52 So, the lamin A is permanently attached.

    01:55 It cannot detach, we cannot cleave it. You and I, we cleave it.

    01:59 That leads to an unstable nuclear envelope that gets pulled by all of those cytoskeletal elements inappropriately.

    02:06 And when there's abnormal nuclear shape, instead of being a round or oval structure, it's indented. It's contorted. It's bizarre-looking.

    02:15 And when that happens, we pull the chromatin open by mechanical forces.

    02:20 So, we go from heterochromatin to euchromatin, and we get abnormal transcription because of this defect of a lamin protein, and it's just one amino acid.

    02:30 So, it's abnormal nuclear shape and chromatin organization.

    02:34 And this just gives you an example.

    02:36 This is just an immunofluorescence study looking at the nucleus and the nuclear membrane in a normal cell on the left and that contorted, distorted nuclear envelope that happens in a lamin A mutation in a patient with Hutchinson-Gilford progeria.

    02:53 And you get abnormal transcription which leads to the premature senescence of cells, which leads to the phenotype that we saw on the previous slide.

    About the Lecture

    The lecture Resulting Condition: Hutchinson-Gilford Progeria by Richard Mitchell, MD, PhD is from the course Cellular Housekeeping Functions.

    Included Quiz Questions

    1. Lamin A
    2. Helicase
    3. Telomerase
    4. DNA topoisomerase
    5. DNA polymerase III
    1. Accelerated atherosclerosis
    2. Obesity
    3. Photosensitivity
    4. Cognitive dysfunction
    5. Hirsutism

    Author of lecture Resulting Condition: Hutchinson-Gilford Progeria

     Richard Mitchell, MD, PhD

    Richard Mitchell, MD, PhD

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