Chapter 7, Problem 1NST

Campomelic dysplasia (CMD1) is a congenital human syndrome featuring malformation of bone and cartilage. It is caused by an autosomal dominant mutation of a gene located on chromosome 17. Consider the following observations in sequence, and in each case, draw whatever appropriate conclusions are warranted.

1. (a) Of those with the syndrome who are karyotypically 46, XY, approximately 75 percent are sex reversed, exhibiting a wide range of female characteristics.
2. (b) The nonmutant form of the gene, called SOX9, is expressed in the developing gonad of the XY male, but not the XX female.
3. (c) The SOX9 gene shares 71 percent amino acid coding sequence homology with the Y-linked SRY gene.
4. (d) CMD1 patients who exhibit a 46, XX karyotype develop as females, with no gonadal abnormalities.

HINT: This problem asks you to apply the information presented in this chapter to a real-life example. The key to its solution is knowing that some genes are activated and produce their normal product as a result of expression of products of other genes found on different chromosomes.

Summary Introduction

To determine: The explanation for the sex reversal in Campomelic dysplasia (CMD1).

Introduction: The mutation is the change in the nucleotide sequence of the gene, which result in either the formation of a defective protein or no protein at all. The mutation can also alter the regulation of certain genes leading to their hyperactivity or hypoactivity.

Explanation of Solution

The individuals with Campomelic dysplasia contain an autosomal dominant mutation in chromosome number 17. The disease causes the malformation of bone and cartilage. The karyotype of the patients with this disorder is 46 chromosomes with X and Y sex chromosomes. The individual thus cannot show typical sexual differentiation. This is because gene CMD1 plays an important role in controlling sexual differentiation. The mutation in the gene can interfere with the transcription, translation, or the receptor functioning of genes responsible for male sex differentiation. Therefore, the individual can exhibit some female characteristics.

Summary Introduction

To determine: The reason for the expression of the non-mutant form of SOX9 in gonads of male and not females

Introduction: Genetic abnormality can take place when there is any alteration in the gene expression or the nucleotide composition. The typical effect of genetic change is the decrease in the fertility of the affected individual.

Explanation of Solution

The non-mutant gene SOX9 is present in an individual without Campomelic dysplasia. This finding indicates that the gene SOX9 is responsible for the development of the gonads in males. This gene is not found in the females having XX chromosomes, and so the gene does not play any significant role in the sex differentiation in females.

Summary Introduction

To determine: The reason for 71% homology between SOX9 gene and Y-linked SRY gene.

Introduction: Homology is the degree of similarity between the genes, proteins, or other biomolecules. The homology can be attributed to the similar ancestry or the same point of origin of the molecules or structures.

Explanation of Solution

The SOX9 gene shares high similarity or homology (71%) with the SRY gene. The high degree of similarity can account for the similar functions shared between the genes. As the Y-linked SRY gene plays a role in male sex differentiation, the similarity in the genes can explain the function of SOX9 gene in the development of undifferentiated gonadal tissue into testes.

Thus, the high degree of similarity between the Y-linked SRY gene and SOX9 gene indicates the similarity in the function and role in male sex differentiation.

Summary Introduction

To determine: The reason for the CMD1 female patients exhibiting 46, XX karyotype with no gonadal abnormalities.

Introduction: Karyotype is the representation of the genetic composition in an individual. It is expressed as the total number of chromosomes followed by the composition of sex chromosomes and genetic abnormality if it is present.

Explanation of Solution

The individual with Campomelic dysplasia with the karyotype 46, XX will develop into a female and will not exhibit any gonadal abnormalities. This is because the SOX9 gene that gets mutated and hampers the sexual differentiation is only in males and not in females. The SOX9 gene does not play any role in the female sex differentiation. Therefore, the alterations in this gene will not cause any gonadal abnormalities in females due to the absence of its function in female gonad development.

Thus, the female with CMD1 will not have any gonadal abnormalities as the SOX9 gene that gets mutated does not play a role in sexual differentiation in females.