Genetics

Molecular genetics and inheritance of MPS I

The 19-kb gene encoding α-L-iduronidase (IDUA) is located on chromosome 4. Over 100 different IDUA gene mutations causing MPS I have been identified, including insertions/deletions and nonsense, missense and splice site mutations. Some of these mutations are “private”, or restricted to single families.1

The IDUA gene follows an autosomal recessive pattern of inheritance.2 Thus an individual must inherit two disease-causing mutations (alleles), one from each parent, to be affected by the disease. Males and females are equally affected. Individuals with only one mutant allele are unaffected carriers. There is a 1 in 4 chance with each pregnancy that a carrier couple will have an affected child. Children of affected individuals are always carriers of MPS I, unless the other parent is a carrier in which case there is a 1 in 2 chance with each pregnancy of having an affected child. 

Autosomal recessive inheritance of MPS I

Predicting MPS I severity based on genotype

Three IDUA alleles, W402X, Q70X and P533R, account for over half of all MPS I alleles in the Caucasian population but have never been detected in some other ethnic populations.3 The W402X and Q70X alleles are nonsense mutations and, like all other known nonsense mutations, do not produce any functional enzyme. Homozygosity or heterozygosity for nonsense alleles results in severe MPS I.1 Although it is widely accepted that the clinical heterogeneity of MPS I is caused by different combinations of mutations that result in varying levels of residual enzyme activity, phenotype cannot be reliably predicted in individuals with other mutations.1

Molecular genetics and inheritance of MPS II

The 24-kb gene encoding iduronate-2-sulphatase (IDS) is located on the X chromosome.3 Over 330 IDS gene mutations causing MPS II have been identified. Many are restricted to single families.4 The most common mutations are point mutations (missense, nonsense, frameshift, altered splice sites) or small deletions/insertions.3 Large deletions and rearrangements are found in a fifth of individuals with MPS II.5

MPS II is the only MPS disorder that is inherited an X-linked recessive manner. Thus MPS II is a disorder generally restricted to males.3 Females are unaffected carriers of the disorder, except in rare circumstances (see below). There is a 1 in 2 chance with each pregnancy that a female carrier will pass the mutant gene on to her child. All sons who inherit the gene will be affected and all daughters who inherit the gene will be carriers.

X-linked recessive inheritance of MPS II3

 

Rare cases of MPS II in females

As an X-linked recessive disorder, MPS II generally does not affect females. Although the disease could manifest in the daughter of an affected male and a female carrier, affected males generally do not reproduce. Manifestation of MPS II in females is usually attributed to non-random X chromosome inactivation of the non-mutant allele in heterozygotes.3 In most cases the mutant gene has been inherited from a carrier mother and the non-mutant paternal allele has been preferentially inactivated, resulting in expression of the mutant maternal allele. De novo mutation in one allele in combination with inactivation of a mutant allele has also been reported in females with MPS II.6

Predicting MPS II severity based on genotype

The high prevalence of private mutations in patients with MPS II has made genotype-phenotype correlations difficult.4 Large deletions and rearrangements in the IDS gene are predictive of severe Hunter syndrome (an alternative name for MPS II). These are null mutations that do not produce any enzyme.4,5 However, the majority of patients have small mutations, which can result in phenotypes ranging from mild to severe.

 

References

  1. 1.Terlato NJ, Cox GF. (2003) Can mucopolysaccharidosis type I disease severity be predicted based on a patient's genotype? A comprehensive review of the literature. Genet Med 5(4): 286-294.
  2. 2.Scott HS, Bunge S, Gal A, Clarke LA, Morris CP, Hopwood JJ. (1995) Molecular genetics of mucopolysaccharidosis type I: diagnostic, clinical, and biological implications. Hum Mutat 6(4): 288-302.
  3. 3.Neufeld EF, Muenzer J. The Mucopolysaccharidoses In: Valle D, Beaudet AL, Vogelstein B, Kinzler KW, Antonarakis SE, Ballabio A, et al., editors. The Online Metabolic and Molecular Bases of Inherited Disease. New York, NY: McGraw-Hill; 2014.
  1. 4.Burton BK, Giugliani R. (2012) Diagnosing Hunter syndrome in pediatric practice: practical considerations and common pitfalls. Eur J Pediatr 171(4): 631-639.
  2. 5.Hopwood JJ, Bunge S, Morris CP, et al. (1993) Molecular basis of mucopolysaccharidosis type II: mutations in the iduronate-2-sulphatase gene. Hum Mutat 2(6): 435-442.
  3. 6.Tuschl K, Gal A, Paschke E, Kircher S, Bodamer OA. (2005) Mucopolysaccharidosis type II in females: case report and review of literature. Pediatr Neurol 32(4): 270-272.