muscular dystrophy by 0I7aRQVv

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									                                  CHAPTER 16

                              MAMMOTH GENES

                            MUSCULAR DYSTROPHY



DISCUSS:

                    I      GENE SIZES

                    II     WHY ARE SOME GENES SO BIG?

                    III    INTRONS

                    IV     DISADVANTAGE TO LARGE GENES

                    V      PEDIGREE ANALYSIS OF X LINKED RECESSIVE

                    VI     DYSTROPHIN GENE

                    VII    MUTATIONS IN THE DYSTROPHIN GENE

                    VIII   DUCHENNE MUSCULAR DYSTROPHY

                    IX     DYSTROPHIN

                    X      IDENTIFICATION OF THE DMD GENE

                    XI     STRUCTURE AND FUNCTION OF THE DMD GENE

                    XII    BECKER MUSCULAR DYSTROPHY

                    XIII   PRENATAL DIAGNOSIS

                    XIV    TREATMENT

                    XV     GENE THERAPY



ALL MUSCULAR DYSTROPHIES ARE CHARACTERIZED

BY GRADUAL WEAKENING AND WASTING OF MUSCLE TISSUE



DMD

                    DUCHENNE MUSCULAR DYSTROPHY

       ONE OF THE MOST COMMON AND BEST KNOWN GENETIC DISORDERS



I      GENE SIZES




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                     DIPLOID CELL HAS 6 BILLION BASE PAIRS

                     HAVE ABOUT 35, 000 GENES


THESE GENES CAN BE DIVIDED INTO 5 GROUPS BASED ON THEIR SIZE

TABLE 16.1

SMALL         ALPHA AND BETA GLOBIN AND INSULIN              800 – 4000BP
MEDIUM               COLLAGEN AND ALBUMIN PROTEIN                           11 – 45 KB
LARGE                PHENYLALANINE HYDROXYLASE                              50 – 150 KB
GIANT                CYSTIC FIBROSIS                                        160 – 250 KB
MAMMOTH              DMD



II     WHY ARE SOME GENES SO BIG?


       GENE SIZE INCLUDES THE ENTIRE DNA SEQUENCE, PROMOTER AND ALL

       FINAL MRNA PRODUCT THAT MAKES A PROTEIN HAS BEEN SPLICED AND PROCESSED

DMD

GENE EXTENDS 2.5 MILLION BASES

       LARGEST GENE EVER KNOWN

              1% OF TOTAL SEQUENCE                EXONS

              99% OF THE CODING SEQUENCE          INTRONS


DMD GENE STILL HAVE A VERY LARGE MRNA              17 KB,

              10 TIMES THE SIZE OF AN AVERAGE MRNA

              CODES FOR 3,685 AA



III    INTRONS


       MUCH OF THIS INFORMATION IS NON-CODING SEQUENCES OR INTRONS

        INTRONS ARE MIXED IN WITH THE CODING SEQUENCES OR EXONS

       FIG 16.1 SHOWS A HYPOTHETICAL GENE

       COMPOSED OF 3 EXONS AND 2 INTRONS


       DYSTROPHIN GENE HAS ABOUT 70 INTRONS

       SPLICED OUT BEFORE IT GOES TO THE CYTOPLASM

       INTRONS MAY BE INVOLVED GENE REGULATION




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     CREATE SPACE IN A GENOME THAT BECOMES AVAILABLE FOR THE EVOLUTION OF NEW
     GENES

     HAVING SPACERS BETWEEN THE EXONS

           MAY ALLOW FOR CUT AN PASTE MECHANISMS

           MAKE NEW COMBINATIONS

           GIVE AN ORGANISM A SELECTIVE ADVANTAGE



IV   DISADVANTAGE TO LARGE GENES


            LARGER A GENE IS THE MORE LIKELY IT IS TO BE MUTATED


            MORE LIKELY IT IS TO HAVE PIECES DELETED


           1/3, 500 MALES HAVE A LOSS OF FUNCTION IN THEIR DMD GENE


           1/3 OF THESE MALES ARE NEW MUTATIONS


           NOT MUTATIONS THEY INHERITED FROM THEIR MOTHER


           THEIR MOTHERS ARE NOT CARRIERS


           THE RATE OF MUTATION IN THE DMD GENE IS ABOUT


            1 MUTATION FOR EVERY 10, 000 GAMETES


           10 TO 100 TIMES HIGHER THAN FOR OTHER HUMAN GENES



V    PEDIGREE ANALYSIS X LINKED RECESSIVE


1)   MORE MALES THAN FEMALES AFFECTED.

           THESE MALES ARE HEMIZYGOUS FOR THE ABNORMAL ALLELE


2)   AFFECTED MALES INHERIT ABNORMAL ALLELE FROM MOTHER

           AFFECTED MALES PRODUCE ONLY UNAFFECTED SONS
           AND CARRIER DAUGHTERS.


3)   CARRIER MOTHER WILL PRODUCE

           1/2 AFFECTED SONS AND 1/2 NORMAL SONS




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VI     DYSTROPHIN GENE


       THE LARGEST KNOWN HUMAN GENE

       LOCATED ON THE X CHROMOSOME

              SEX LINKED

       2.5 MILLION BASE PAIRS LONG

              ABOUT 1.5% OF THE LENGTH OF THE X CHROMOSOME

              A VERY LARGE MUTATIONAL TARGET



VII    MUTATIONS IN THE DYSTROPHIN GENE


       MUTATIONS IN THIS GENE CAUSE:

              DUCHENE MUSCULAR DYSTROPHY
              BECKER DYSTROPHY


       NO ONE IMAGINED THAT A SINGLE GENE COULD BE BIG ENOUGH TO ENCOMPASS BOTH OF
       THOSE MUTATIONS



VIII   DUCHENNE MUSCULAR DYSTROPHY


                     X LINKED RECESSIVE DISORDER

                     MOST AFFECTED INDIVIDUALS ARE MALE

                     MALES ARE NORMAL AT BIRTH

                     MAY WALK AND TALK LATE

                     DEVELOP MUSCLE WEAKNESS AT AGE 4 OR 5


ALTHOUGH THE CALF MUSCLES ARE WEAK THEY ARE NOTICEABLE THICKENED


       AS THE SHOULDER, TRUNK AND BACK MUSCLES WEAKEN

       THE CHILD DEVELOPS A SWAYBACK POSTURE AND FALLS A LOT


       CONFINED TO A WHEELCHAIR BY AGE 12


       DEATH IN THE LATE TEENS DUE TO

              MUSCLE WASTING AND DETERIORATION




                                            4
               RESPIRATORY FAILURE WHEN THE DIAPHRAGM MUSCLE BECOMES AFFECTED



IX       DYSTROPHIN


               DMD GENE CODES FOR A PROTEIN CALLED DYSTROPHIN

               THIS PROTEIN IS REQUIRED FOR MUSCLE MAINTENANCE

               PREVENTS MUSCULAR ATROPHY

               AFFECTED MALES LACK THIS PROTEIN AND SO THEIR MUSCLES WASTE AWAY

               CARRIER FEMALES SHOW NO SYMPTOMS



X        IDENTIFICATION OF THE DMD GENE


         DMD GENE MAPS TO

                THE SHORT ARM OF THE X CHROMOSOME

               ON BAND 21

SEVERAL VERY RARE FEMALES WITH FULL BLOWN DMD

ALL OF THESE AFFECTED FEMALES HAD AN ABNORMAL CHROMOSOME

THIS CHROMOSOME WAS THE RESULT OF BREAKAGE

AND FUSION OF TWO PARTS OF NON HOMOLOGOUS CHROMOSOMES


EACH FEMALE HAD A DIFFERENT AUTOSOME JOINED TO AN X CHROMOSOME


ALL CASES THE X CHROMOSOME HAD BROKEN IN THE SAME SPOT

               THE XP 21 BAND OF THE SHORT ARM OF THE X CHROMOSOME


THESE DISCOVERIES PINPOINTED THE DMD GENE TO THE XP 21 REGION


BRUCE BRYER

               DIAGNOSED WITH 4 RARE AND SEVER INHERITED DISORDERS


HE HAD

         DMD                                             MUSCLE DISORDER
         RETINITIS PIGMENTOSA                     EYE DISORDER
         MC LEOD RED CELL PHENOTYPE               ABNORMAL BLOOD TYPE
         CHRONIC GRANULOMATOUS DISEASE            IMMUNE DISORDER


ONLY DMD WAS KNOWN TO BE X LINKED



                                          5
ITS GENE LOCATION WAS STILL A MYSTERY


TINY PIECE DELETED FROM THE SHORT ARM OF HIS X CHROMOSOME


INTERNATIONAL GROUP OF 25 RESEARCH TEAMS ANALYZED DATA ON

       1,346 MALES

SHOWED THAT THE DMD AND BMD MUTATIONS WERE ALLELIC


NORMAL LOCUS WAS GIGANTIC MORE THAN 10 TIMES BIGGER THAN ANY OTHER KNOWN HUMAN
GENE



XI     STRUCTURE AND FUNCTION OF THE DMD GENE


       DMD GENE IS GIGANTIC

                                   2.5 MILLION BP IN LENGTH


       CONTAINS 70 INTRONS

       PRODUCED A 17 KB MRNA TRANSCRIPT

       ENCODES A HUGE PROTEIN KNOWN AS DYSTROPHIN


60% OF LOSS OF FUNCTION MUTATIONS ARE DELETION MUTATIONS

THESE MUTATIONS COMPLETELY PREVENT THE CELL FROM MAKING DYSTROPHIN.



XII    BECKER MUSCULAR DYSTROPHY                  BMD


       MUTATIONS THAT DO NOT COMPLETELY ELIMINATE THE CELL’S ABILITY TO PRODUCE
       DYSTROPHIN


       PRODUCE A MUSCULAR WEAKNESS DISORDER WITH A MORE BENIGN PHENOTYPE KNOWN
       AS BECKER MUSCULAR DYSTROPHY


BMD:

       LATER ONSET

              SYMPTOMS APPEAR BETWEEN 6-18 YEARS OF AGE

       SLOWER PROGRESSION

              MAY BE CONFINED TO A WHEEL CHAIR BY AGE 25 – 30

       LONGER LIFE SPAN



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              MAY LIVE TO BE 40 – 50 YEARS OLD AND HAVE CHILDREN


MOST CASES OF THIS DISORDER ARE INHERITED

BECKER PATIENTS PRODUCE DYSTROPHIN BUT IT IS DEFECTIVE

SEEMS TO BE ABLE TO DETER MUSCLE WASTAGE



XIII   PRENATAL DIAGNOSIS


POSSIBLE FOR MORE THAN 90% OF KNOWN FEMALE CARRIERS


NO AMOUNT OF PRENATAL DIAGNOSIS WILL ERADICATE THE DISEASE

BECAUSE ABOUT 1/3 OF ALL CASES REPRESENT NEW MUTATIONS

MOTHERS OF THESE INDIVIDUALS DO NOT CARRY THE ABNORMAL DMD ALLELE




XIV    TREATMENT


       NO CURE FOR EITHER DMD OR BMD

       NO EFFECTIVE DRUGS ARE AVAILABLE


TREATMENT INCLUDES:

                            SPLINTS AND BRACES

                            PHYSICAL THERAPY

                            ORTHOPEDIC SURGERY



XV     GENE THERAPY FOR MUSCULAR DYSTROPHY


CURE THE DISEASE BY INJECTING FUNCTIONAL DMD GENES INTO THE MUSCLES OF AFFECTED
CHILDREN

GENE IS VERY LARGE AND THAT MAKES THIS HARD

EVEN LOW AMOUNTS OF DYSTROPHIN OF INTERMEDIATE FUNCTION CAN REDUCE SYMPTOMS

SO VERY SMALL AMOUNTS OF FUNCTIONAL PROTEIN MAY OFFER RELIEF

THIS HAS HAD SOME SUCCESS IN MICE

THERE IS A LONG WAY TO GO BEFORE IT CAN BE TRIED IN HUMANS




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