When genes go wrong: Mothers make sons infertile

By Syed Akbar

Mothers too are responsible for certain types of infertility in men. Thus far, only fathers have been held responsible for infertility in the male offspring. This is so because it is the father who transmits the Y or male sex-determining chromosome to the son and the mother does not transmit any male sex chromosome to the male child.
But a study, by the Hyderabad-based Centre for Cellular and Molecular Biology, on Indian men from different linguistic and geographical backgrounds shows that mothers too play a key role in transferring the infertility genes to sons. Mothers, however, do not themselves get affected by these infertility genes.
The CCMB study revealed that mitochondrial DNA, which is inherited by sons from mothers, is contributing to increasing male infertility around the world, particularly in men from the Indian sub-continent. The mitochondrial or mDNA is found to be undergoing mutations affecting the motility of sperm as well as its count.
“Sperm quality is also greatly influenced by mutations in the components of the respiratory chain of the mitochondrial DNA. Although mDNA has been studied extensively for the past two decades, very few studies have investigated the involvement of mDNA mutations in male infertility. There are 37 genes in mDNA, encoding 13 proteins, which are essential components of respiratory-chain complexes involved in the production of adenosine triphosphate,” says Dr Kumarasamy Thangaraj of Evolutionary and Medical Genetics Laboratory of the Centre for Cellular and Molecular Biology.
As part of the study, the CCMB team analysed the mitochondrial DNA of 34 men suffering from oligoasthenozoospermia (low sperm count with poor motility) along with 150 normozoospermic (fertile) men. The team noticed a novel missense mutation in ND4 gene. A missense is a mutation that converts a codon coding for one amino acid to a codon coding for another amino acid. In the case of oligoasthenozoospermic men, the mutation in the ND4 gene replaced threonine with isoleucine. But this was not observed in normozoospermic or fertile men who served as a control group for purpose of the study.
Dr Thangaraj points out that abnormal semen is one of the major factors that is associated with male infertility. The quality and quantity of sperm production may be affected greatly by both environmental and genetic factors. Karyotypic (chromosomal) abnormalities and Y-chromosomal microdeletions are the most frequent genetic abnormalities associated with abnormal semen profile, particularly oligozoospemia (less than 20 million sperm per ml but still a measurable level) nonobstructive azoospermia (a condition with complete lack of measurable sperm).
Explaining how the mitochondrial DNA from mothers is responsible for infertility in sons, he says spermatozoa are heavily dependent on mitochondria for respiratory energy for motility. The mature mammalian spermatozoon contains about 72 to 80 mitochondria in the mitochondrial sheath of the midpiece (area below the sperm head which serves as a motor of the sperm).
Analysis of blood samples from both oligoasthenozoospermic (infertile) and normozoospermic (fertile) control men revealed the presence of several sequence variants but one variant at nucleotide position was found to be present in all 10 samples. Interestingly the T allele (C11994T) never before has been reported, either as a polymorphism or in association with a disease, anywhere in the world.
“We screened for the presence of this mutation in the remaining 24 samples. Amazingly, we also found this mutation in all the remaining 24 samples, although none of the 150 proven-fertile (normozoospermic) men carried it. The C11994T mutation is located in the second base of a codon, resulting in an amino-acid change from threonine to isoleucine at amino-acid position 412 of the ND4 gene. The ND4 gene is an essential subunit of complex I of the mitochondrial respiratory chain, and ND4 mutations have been implicated in mitochondrial diseases such as Leigh’s syndrome and Leber hereditary optic neuropathy,” he observed.
Because none of the fertile men analysed in this study or in other studies around the world has been found to contain this C11994T mutation, the possibility of it being a neutral polymorphism was ruled out by the CCMB team.
“There is interesting evidence that mDNA variation is an important contributor to the motility variation of sperm. Mutations of mDNA have been well documented in several disorders, either independently or in association with nuclear mutations,” Dr Thangaraj says.