Autosomal dominant inheritance, Mendelian inheritance.

1. Achondroplasia
Autosomal Dominant
Inheritance, Mendelian
Inheritance.
P R E S E N T E D B Y :
N A D I A A B D A L M O H S E N A L A N Z I
M O L E C U L A R P A T H O L O G Y , C E L L U L A R A N D M O L E C U L A R P A T H O L O G Y M A S T E R S T U D E N T
ACHONDROPLASIA 1

2. ACHONDROPLASIA 2
Presentation Outline
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3. Background
Achondroplasia (ACH)
 Is inherited as an autosomal dominant, is the most common
cause of disproportionate short stature and other skeletal
anomalies resulting from a defect in the maturation of the
chondrocytes in the growth plate of the cartilage. Affected
individuals have rhizomelic shortening of the limbs,
macrocephaly, and characteristic facial features with frontal
bossing and midface retrusion.
ACHONDROPLASIA 3

4. ACHONDROPLASIA 4
Molecular pathology
 Achondroplasia is caused by a mutation in fibroblast growth factor receptor 3 (FGFR3)
gene on chromosome region 4p 16.3 .
 Normal product gene: This gene is mainly responsible for making the protein, fibroblast
growth factor receptor 3 . This protein contributes to the production of collagen and other
structural components in tissues and bones.
 Abnormal product gene: When the FGFR3 gene mutated is hyperactivated, resulting in
the inhibition of growth of cartilage cells and disturbances in bone growth. Two mutations
are commonly observed in the FGFR3 gene. Both mutations (G>A; G>C) result in a glycine
to arginine substitution. Cartilage is not able to fully develop into bone, causing the
individual to be disproportionately shorter in height.

5. ACHONDROPLASIA 5
Diagnosis
• Ultrasound examination may identify short fetal limbs.
• Prenatal diagnosis using cell-free fetal DNA in maternal serum.
• Genetic counseling.

6. ACHONDROPLASIA 6
Molecular technology
Achondroplasia in a nonconsanguineous Pakistani family

7. ACHONDROPLASIA 7
Molecular technology
• The ACH family pedigree and DNA sequence
analysis:
(a) Pedigree of a non-consanguineous Pakistani
family where ACH is segregating as dominant
trait. Three affected individuals (II-3, III-1, III-2)
and three phenotypically healthy individuals (II-
1, II-2, II-4) were analysed. b Sanger sequencing
of FGFR3 gene revealed a G > A heterozygous
substitution mutation in affected individuals. c
PCR-RFLP analysis; an electrophoretic banding
pattern of SfcI digestion revealed heterozygous
condition in sizes 545 bp, 313 bp and 232 bp of
affected individuals.

8. ACHONDROPLASIA 8
For more information
Kai miao, xin zhang, sek man su, jianming zeng, zebin huang, un in chan, xiaoling xu
and chu-xia deng, optimizing CRISPR/cas9 technology for precise correction of the
fgfr3-g374r mutation in achondroplasia in mice, journal of biological chemistry,
10.1074/jbc.Ra118.006496, 294, 4, (1142-1151), (2018).
PAULI, R. M. & LEGARE, J. M. 1993. Achondroplasia. In: ADAM, M. P., ARDINGER,
H. H., PAGON, R. A., WALLACE, S. E., BEAN, L. J. H., STEPHENS, K. & AMEMIYA, A.
(eds.) GeneReviews((R)). Seattle (WA).
AJMAL, M., MIR, A., SHOAIB, M., MALIK, S. A. & NASIR, M. 2017. Identification
and in silico characterization of p.G380R substitution in FGFR3, associated with
achondroplasia in a non-consanguineous Pakistani family. Diagn Pathol, 12, 47.

9. Thank You!
‫ثروتنا‬‫األولى‬‫التي‬‫ال‬‫تعادلها‬‫ثروة‬‫مهما‬‫بلغت‬:‫شعب‬‫طموح‬،‫معظمه‬‫من‬‫الشباب‬،‫هو‬‫فخر‬‫بالدنا‬‫وضمان‬‫مستقبلها‬‫بعون‬‫هللا‬..‫األمير‬‫محمد‬‫بن‬
‫سلمان‬.
TEACH A COURSE 9