In a recent report, 13 of 21 children with mucopolysaccharidosis type IIIA (MPS IIIA), documented enzyme deficiency and SGSH gene mutations that were evaluated with the Autism Diagnostic Observation Schedule (ADOS) (module 1) met the ADOS criteria for ASD/autism (Rumsey et al., 2014).
Molecular Function
This gene encodes one of several enzymes involved in the lysosomal degradation of heparan sulfate. Mutations in this gene are associated with Sanfilippo syndrome A, one type of the lysosomal storage disease mucopolysaccaridosis III, which results from impaired degradation of heparan sulfate [MPS IIIA; MIM:252900].
External Links
References
Type
Title
Type of Disorder
Associated Disorders
Author, Year
Primary
Acquired autistic behaviors in children with mucopolysaccharidosis type IIIA.
Sgsh homozygous knockout mouse models show autistic-like behaviors due to increased proliferation of mesencephalic dopamine neurons originating during embryogenesis, which is not due to lysosomal dysfunction, but due to altered HS (heparan sulfate) function. Treatment with the dopamine D1-like receptor antagonist SCH-23390 restores hyperdopaminergia and autistic-like behaviors (De Risi M, et al, Nat. Commu. 2021).
References
Type
Title
Author, Year
Primary
Altered heparan sulfate metabolism during development triggers dopamine-dependent autistic-behaviours in models of lysosomal storage disorders
Model Type:
Genetic LOF
Model Genotype:
Homozygous
Mutation:
Spontaneous mutation resulting in a g-to-a transition point mutation at coding nucleotide 91 of the encoded mrna (c.91g>a) altered the corresponding amino acid from aspartic acid to asparagine at position 31 of the encoded protein (p.d31n).
Allele Type: Missense mutation
Strain of Origin: 129X1/SvJ * CD-1 * C57BL/6 * SJL
Genetic Background: C57BL/6
ES Cell Line: NA
Mutant ES Cell Line: NA
Model Source: 11181566
Description: Increased expression of tyrosine hydroxylase and dopamine at 2-months, and p28 striatum; hyperdopaminergia; increased th+ dendritic arbors in the substantia nigra; ; no change in the number of th+ neurons in 8-month-old mutant mice; th levels in the striatum of mps-iiia mice at 8 months is reduced; early onset
Description: Increased expression of d1r at 2 months in the nucleus accumbens and dorsomedial striatum but not in the dorsolateral striatum; d2r pre-synaptic expression is decreased in striatum; d2r postsynaptic expression is increased; early onset
Description: Increased expression of tyrosine hydroxylase and dopamine in 2-month-old striatum; hyperdopaminergia; th levels in the striatum of mps-iiia mice at 8 months is reduced; early onset
Description: Autophagosome/lysosomal dysfunction as evidenced by increased lc3-ii protein expression and an increase of one of its protein substrates, sequestosome 1 (p62/sqstm1)
Description: Increased number of cleaved caspase 3 and most th+ cells expressed both nuclear and perinuclear cc3+ spots at 8 months; at 2 months no cells were positive for cc3+; late onset
Description: Autophagosome/lysosomal dysfunction as evidenced by increased lc3-ii protein expression and an increase of one of its protein substrates, sequestosome 1 (p62/sqstm1)
