doi:10.1016/S0002-9297(07)61961-2


Am. J. Hum. Genet. 73:i–ii, 2003

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This Month in the Journal
Yin Yang Haplotypes in the Human Genome, by
Zhang et al. (p. 1073)

While working on the identification of haplotype-tagging
SNPs using chromosome 21 data, Zhang et al. stumbled
across an interesting phenomenon that they dub “yin yang
haplotypes.” These pairs of high-frequency haplotypes are
composed of completely mismatched SNP alleles; that
is, they differ from each other at every SNP position. To
study these divergent haplotypes in a more systematic
manner, Zhang et al. developed an algorithm to identify
regions containing yin yang haplotype pairs and used it
to characterize two genomewide data sets. They found
that 75%–85% of the human genome is spanned by yin
yang haplotypes and that these haplotypes make up a
significant portion of the total haplotype diversity. Higher
coverage with yin yang haplotype was achieved after re-
moval of low-frequency SNPs from the analysis, which
led the authors to suspect that these haplotypes are an-
cient. Further supporting this idea is the high degree of
conservation of yin yang haplotypes across populations,
suggesting these patterns emerged prior to the African
diaspora. Although it might seem that evolution must
have had a hand in the rise of opposing haplotype alleles,
simulations indicate that yin yang haplotypes can occur
under a neutral evolution model.

g-Actin Gene Mutations and Progressive Deafness, by
Zhu et al. (p. 1082)

Because mutations in several genes encoding actin-inter-
acting proteins have been found to cause hearing loss, it
is perhaps not surprising that Zhu et al. report mutations
in the gene for g-actin itself in four families with pro-
gressive deafness. What is unexpected, though, is the fact
that, when this protein is widely expressed and highly
conserved, the only phenotype in the affected individuals
is hearing loss. All four mutations are missense mutations
at conserved residues, and they occur in three of the four
subdomains of the g-actin protein. Zhu et al. speculate
that the mutations have mild effects on protein function
and that the auditory hair cells may be more sensitive to
mutations in this gene because they do not regenerate, so
subtle mutations can have long-term effects. This is
in contrast to other g-actin–expressing tissues in which
cells are regenerated frequently, such as the intestinal epi-
thelium. Hair cells may also be more susceptible to these
mutations than other g-actin–expressing cells because
their function is dependent on precise control of their

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ultrastructural organization, which is determined by the
actin cytoskeleton.

Mutations and Clinical Correlations in XLRP, by
Sharon et al. (p. 1131)

In an attempt to define genotype-phenotype correlations
in X-linked retinitis pigmentosa (XLRP), Sharon et al.
screened RP2 and RPGR for mutations in a large sample
of males with a diagnosis (or a suspected diagnosis) of
XLRP or cone-rod degeneration. Mutations were found
in 79% of the 135 people with a prior clinical diagnosis
of XLRP, with the most common location being ORF15
of RPGR, a region that was overlooked in initial screens
of this gene. Although there is a good deal of overlap in
measures of ocular function, people with RP2 mutations
have, on average, a significantly lower visual acuity than
patients with RPGR mutations. Subgroup analyses of the
people with RPGR mutations indicate that those with
ORF15 mutations have milder disease than those with
mutations in exons 1–14. Within this ORF15 mutation
group, the severity of the visual effects depended on the
length of the wild-type amino acid sequence expressed.
Confirming a previous report, mutations in ORF15
downstream of codon 445 were often associated with
cone-rod degeneration rather than a strict XLRP pheno-
type, suggesting that these mutations are more deleterious
to cones than to rods. These findings move us toward the
ultimate goal of this research, which is to make mutation-
based, long-term visual prognoses, but the heterogeneity
in visual impairment within the mutation groups does not
yet make this fully possible.

Mapping and Cloning the Gene for Mast Syndrome,
by Simpson et al. (p. 1147)

In a recent Journal editorial, Crosby and Proukakis (71:
1009–1016) proposed that a common underlying mech-
anism in some hereditary spastic paraplegias (HSPs) may
be a defect in cellular transport. Now, with the finding
that mutations in ACP33 are found in people with Mast
syndrome, Simpson et al. believe they have found addi-
tional evidence for this model. Mast syndrome is a com-
plicated form of autosomal recessive HSP that is found
in Old Order Amish. The disorder is progressive, and
onset generally occurs in young adults, although milestone
delays and subtle cognitive and motor difficulties are often
reported in childhood. Through use of a large Amish pedi-
gree, Simpson et al. identified a single-nucleotide insertion
in ACP33 that leads to premature truncation of the en-
coded protein. ACP33 was originally identified as a CD4-



Am. J. Hum. Genet. 73:i–ii, 2003

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interacting protein that appears to regulate CD4-depen-
dent T cell activation (see Zeitlmann et al. reference in
Simpson et al.). The protein is partitioned between the
cytoplasm and the endosomal/trans-Golgi network, and
it has been proposed that it may be involved in intra-
cellular trafficking and protein sorting. The HSPs result
from degeneration of the longest motor and sensory axons
in the spinal cord. Dr. Crosby’s group has speculated
that, because of their size, these axons are particularly
susceptible to disruption of intracellular trafficking pro-
cesses, which are vital for neuron survival. They propose
that the ACP33 gene product should be renamed “mas-
pardin” for “Mast syndrome, spastic paraplegia, autoso-
mal recessive with dementia.”

PTEN Mutations Upregulate Akt in LDD, by Zhou et
al. (p. 1191)

PTEN mutations cause a variety of disorders, including
Proteus syndrome, Bannayan-Riley-Ruvalcaba syndrome,
and Cowden syndrome (CS). The explanation for pheno-
typic differences in the expression of PTEN mutations
and the relationship between these syndromes has not
been fully uncovered. Lhermitte-Duclos disease (LDD) is
another disorder associated with PTEN mutations, and
it often occurs in association with features of CS, sug-
gesting that these disorders share a common etiology. CS

is characterized by multiple hamartomous lesions and
typically involves neoplasms of internal organs, whereas
LDD is a hamartomous overgrowth of hypertrophic gan-
glion cells. To better understand the relationship between
CS and LDD, Zhou et al. gathered 18 subjects with
LDD, without regard to the presence or absence of other
features in these individuals, and performed mutational
analysis on PTEN. They discovered 16 PTEN mutations
in 15 adult-onset cases, both with and without features
of CS. On the basis of six matched germline DNA sam-
ples, at least these six were germline mutations. Several
points suggest that loss of PTEN is sufficient to cause
LDD and that LDD is a component of CS. These include
the high frequency of PTEN mutations, the complete or
partial loss of PTEN staining in ∼75% of samples, and
the identification of loss of heterozygosity or a second-
hit somatic PTEN mutation in three cases. In contrast
to the mutations in the adult-onset cases, all three child-
hood LDD cases lacked PTEN mutations, both somatic
and germline. In conjunction with three other reported
patients with childhood LDD who never developed fea-
tures of CS, this finding makes the interesting suggestion
that adult-onset and childhood LDD may be distinct dis-
orders, although this will require further study.

KATHRYN GARBER
Deputy Editor