Inheritance of MTHFR Deficiencies

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Both the severe and mild deficiencies of MTHFR show autosomal recessive inheritance patterns (Rosenblatt & Erbe, 1977). This work has been supported by pedigree studies, as outlined below. 

Since the gene for the MTHFR protein was not found using traditional linkage studies, pedigree analysis was not done or used until after its location was already known. However, some research groups constructed pedigrees for families that had MTHFR deficiency in order to link the deficiency to other health problems that may have been transmitted through the generations. For example, the following pedigree was used to verity the transmission of two specific mutations in this particular family.

Sequencing and restriction enzyme digest did indeed show that the four children were homozygous for both mutations. At the 677bp, most people are C/C in absence of a mutation. However, the father was T/T (based on the C to T bp substitution) and the mother was heterozygous C/T. Although not the only possibility, all of the children born were homozygous for the mutation, T/T. In addition, the other mutation at the 1081 bp is also C/C wild-type. However, both parents were C/T (again representing the substitution in the base pairs from C to T). Unfortunately, the T allele was passed on by both parents to all four of their children, giving them all the T/T genotype. Interestingly, both parents had normal health throughout their lives and no noticeable deficiency in their MTHFR enzyme. Nevertheless, all of their children have had persistent health problems typical of MTHFR deficiency (seizures, developmental delays, lack of speech/communication, gait abnormalities, etc.). Furthermore, their fourth child died at 2 months of severe pneumonia and respiratory failure, even though the parents had attempted to do prenatal diagnosis (on chorionic villi and trophoblast), which only revealed slightly lower MTHFR activity. In analyzing the different alleles, it was found that the wild-type allele at the 677 bp generate a 198 bp fragment when digested with Hinf I. However, the CT substitution creates a new recognition site that splits that fragment into a 175 and 23 bp fragments (seen in Gel 1). For the 1081 bp wild-type gene, a Hha I digestion typically yields a 152 bp fragment. Then, with this CT mutation, that Hha I site disappears and the digestion of these alleles reveals a slightly longer 165 bp fragment (seen in Gel 2). (Analysis from Tonetti et al 2000). This general algorithm that linked mutations to altered restriction enzyme recognition sites (and hence, fragment lengths on gels) was also used in other families to first determine specific mutations and then to identify them in other individuals both related and non-related.