The human genome is composed of 30,000 unique genes. Each gene is composed of a promotor or regulator region, and a transcriptional or coding region. Regulatory proteins or transcription factors bind to the promoter region of the gene to signal the beginning of transcription of the DNA into RNA or repress the expression of the gene. The coding region contains both introns and exons. Exon sequences of the gene directly code for the proteins, and the introns are spacers. The intron sequences are enzymatically removed from the newly transcribed messenger RNA by a splicing mechanism (Puzas).
- 46 chromosomes
- 150,000 genes per chromosome
Four proteins that regulate osteoclast activation have been discovered (Puzas):
- Receptor activator of nuclear factor -kB (RANK) binds to a receptor on osteoclast precursor cells and positively effects their final differentiation into osteoclasts.
- Osteoprotegerin is a soluble decoy receptor that resembles RANK and inhibits osteoclasts.
- Tumor necrosis factor-related activation induced cytokine (TRANCE)
- Osteoclast differentiation factor
- Cbfa1 is a transcription factor (coded by the Cbfa1 gene) that is necessary and sufficient for differentiation of cells into osteoblasts and facilitates chondrocyte differentiation during enchondral bone formation.
Mendelian Inheritance (Milla)
One should remember that there are 4 inheritance patterns:
The important points are:
Autosomal dominant - Patients with autosomal dominant disorders usually have a structural defect, such as achondroplasia, Marfan's syndrome, or Ehlers-Danlos syndrome.
Autososmal recessive - Patients with autosomal recessive disorders usually have a biochemical or enzymatic defect, such as sickle cell disease, Gaucher's disease, or hypophosphastasia.
Questions may be asked on the probability of transmitting a condition. These questions can be figured out by understanding how to use the Pennett squares, or one can memorize the patterns.
Autosomal dominant and recessive
For autosomal dominant, if one parent is a heterozygote and the other is normal, then the risk of transmission will be to 50% of the offspring. Because of the dominance of the allele, heterozygotes manifest the condition.
For autosomal recessive, parents are usually not affected because they are heterozygotes. The risk of transmission will be to 25% of the offspring. The children must have both recessive alleles to be affected.
X-linked dominant and recessive
With X-linked dominant, heterozygotes will have the condition. If a woman has this condition, then she will transmit it to 50% of her sons and daughters.
In contrast, an affected man will transmit the condition to all of his daughters (because the daughter gets his X chromosome), but to none of the sons because the son gets the Y chromosome.
With X-linked recessive, the patterns are different between women and men.
X-linked recessive woman: An X-linked woman with the recessive allele is a carrier, but she is not affected because the allele is recessive.
Carrier females (X-linked recessive) transmit the condition to 50% of her daughters (who become carriers) and 50% of her sons who are then affected (the sons are affected because their only X chromosome has the recessive gene).
Table 1. Common Inheritance Patterns.
||Hemophilia (A, B)
||OI (II, III)
||Duchennes muscular dystrophy
||Becker’s muscular dystrophy
Abbreviations: OI (I,IV)=Osteogenesis imperfecta, SED=Spondyloepiphyseal dysplasia, MED=Multiple epiphyseal dysplasia, MHE=Multiple hereditary exostosis
Table 2. Conditions with Defined Defects.
||Fibroblast growth factor 3 (FGF-3) (receptor)
||Sulfate transporter gene
||G(salpha) protein (receptor)
|Multiple epiphyseal dysplasia
||Cartilage oligomeric protein
||Type II collagen (Col 2A1)
|Type X collagen
||Core binding factor alpha 1 (Cbfa1)
||Type I collagen (Col 1A1, 1A2)
|Albright hereditary osteodystrophy
|End-organ resistance to parathyroid hormone
||Carbonic anhydrase type II, proton pump
||COL 1A2 (type VII)
||Cystathionine beta synthetase
- Dietz FR, Murray JC. Update on the genetic basis of disorders with orthopaedic manifestations. In: Buckwalter JA, Einhorn TA, Simon SR, eds.Orthopaedic Basic Science: Biology and Biomechanics of the Musculoskeletal System. 2nd ed. Rosemont, Ill: American Academy of Orthopaedic Surgeons; 2000:112-131.
- Miller MD. Cellular and molecular biology, immunology, and genetics of orthopaedics. In:Review of Orthopaedics. Philadelphia, Pa: WB Saunders; 2004:86-99.
- Puzas JE, O'Keefe RJ, Lieberman JR. The orthopaedic genome: What does the future hold and are we ready?J Bone Joint Surg Am. 2002; 84:133-141.