By: Melisa Robinson

The most common form of human short limbed dwarfism

Literally means without cartilage formation
Defective endochondral ossification
Symptoms
Average sized trunk with rhizomelic shortening of the
arms and legs
Macrocephaly (enlarged head) and midface hypoplasia
Trident configuration of hands
Normal intelligence
Resulting conditions

sleep apnea
Genu varum (bowed legs)
lordosis or kyphosis of the spine
spinal stenosis

Occurs in 1/25,000 births

Dominant Gain-of-function mutation
Heterozygous mutation causes ACH
Homozygous mutation is lethal
80% of cases are de novo mutations
linked to paternal germline
one of the most mutable nucleotides in the genome
Majority of other cases are inherited from an affected parent
50% chance that a living child will be affected

Mutation in the FGFR3 gene

Located at chromosome 4p16.3
Codes for the FGFR3 protein- a transmembrane tyrosine kinase
receptor
3 domains- an extracellular ligand-binding domain, a transmembrane
domain and an intracellular split tyrosine kinase domain

Mutation occurs within the transmembrane domain

GA or GC point mutation at nucleotide 1138
Causes a p.G380R missense mutation

G380R substitution causes ligand independent

stabilization of FGFR3 dimers
Due to hydrogen bonds formed between the 2 side chains of
the arginine residues

Fibroblast growth factor receptor 3

FGFR3 is activated by FGF ligands
Normal physiological function is the regulation of cartilage growth- ERK
and MAPK pathway
A negative regulator of skeletal growth
restricts the length of the long bones via inhibition of chondrocyte
proliferation

With an ACH mutation, the FGFR3 receptor no longer requires a

ligand to activate.
Constitutive activation- receptor is constantly signaling for ERK activation
and activation of p38 arms of the MAPK pathway

Sustained ERK activiation is associated with decreased

chondrocyte proliferation and extracellular matrix production,
increased matrix degradation, and altered cell shape and
differentiation
MAPK signals not only negatively influence proliferation but
also disrupt terminal differentiation and post-mitotic matrix
synthesis

Multiple Disorders from various mutations within the FGFR3 gene

Five different forms of skeletal dysplasia

Hypochondroplasia, Achondroplasia, SADDAN dysplasia, Thanatophoric dysplasia, &

Platyspondylic Lethal skeletal dysplasia

Also linked to epidermal nevi, seborrhoeic keratosis, acanthosis

nigricans caused by keratinocyte overgrowth, and various forms of
cancer

A genetic paradox
Why do mutations cause inhibition of proliferation in chondrocytes,
but have a mitogenic effect on many other types of cells?
Fibroblasts, keratinocytes, melanocytes, epithelial cells, lymphocytes,
and spermatocytes all increase in proliferation in response to a mutation

Currently, the only treatments available are designed to

manage symptoms after they manifest
Bilateral limb lengthening
Neurosurgery to correct spinal malformations
In the early 2000s, treatments using Human Growth
Hormone (HGH) injections to counteract the downregulation
of ossification began
Treatments saw early success, then failed to cause a
significant increase in bone length
Developing Treatments
Targeting the FGFR3 protein
interfere with FGFR3 synthesis, block its activation,
inhibit its tyrosine kinase activity, promote its
degradation, and antagonize its downstream signals

CNP antagonizes FGFR3 downstream signaling by inhibiting the

ERK/MAPK pathway
A paracrine/autocrine factor that signals through natriuretic
peptide receptor B and modulates the activity of FGFR3
Enhances and restores chondrocyte proliferation and
differentiation which results in bone growth
Studied in mice and cynomolgus monkeys

Many CNP variants limited as a treatment due to rapid clearance

rates by natriuretic clearance receptors (NCR) and neutral
endopeptidase (NEP)
BMN-111 has extended serum half-life due to resistance to NEP
39 amino acid CNP variant
small enough to penetrate successfully to target location
In mouse models, treatment resulted in increased axial and
appendicular skeletal lengths, improvement in ACH-related
clinical features, and correction of growth plate defects
BMN-111 recently completed a successful Phase II clinical trial
26 children in 3 cohorts tested the drug for 6 months
50% increase in growth rate
No serious adverse affects