RESEARCH FRONTIER

MAMLD１（CXorf６）：A New Gene for Hypospadias
Yuka WADA, Maki FUKAMI and Tsutomu OGATA
Department of Endocrinology and Metabolism, National Research Institute for Child Health and Development, Tokyo, Japanand invariably abnormal in six patients with microde-

Introduction. The six patients consist
letions involving MTM1［５―８］Hypospadias is defined by the urethral opening onof three sporadic and three familial cases, and five of

the ventral side of the penis, and is classified into

them have glandular, penile, or penoscrotal hypo-mild glandular or penile type and severe penoscrotal

spadias and the remaining one exhibits ambiguousor perineal type［１］. It is a mild form of ４６, XY disor-. These findings suggest that a gene for
genitalia［５―７］ders of sex development（DSD）, and affects〜０．
５％ of

４
６, XY DSD, especially that for hypospadias, resides

male newborns［２］. Hypospadias is primarily causedin the vicinity of MTM1, and that loss or disruption

by compromised androgen effects, and appears as anof the gene results in the development of ４６, XY

isolated anomaly or in association with other genital

DSD as a consequence of contiguous gene deletion

anomalies such as micropenis and cryptorchidism. To

syndrome.

date, while mutations analyses have been performed

In １
９
９
７, Laporte et al.［９］identified CXorf6 from afor multiple genes involved in androgen effects such４
３
０-kb region deleted in two sporadic cases withas SRD5A2 for ５alpha-redeuctase and AR for andro-

myotubular myopathy and ４
６, XY DSD［７］. CXorf6

gen receptor, pathologic mutations have been identi-

comprises at least seven exons, and harbors an open

fied only in a very small portion of patients［２］. Thisreading frame on exons ３―６ that is predicted to pro-would be consistent with hypospadias being a highly

duce two proteins of ７０
１ and ６
６０ amino acids as aheterogeneous condition subject to multiple genetic

result of in-frame alternative splicing with and without

and environmental factors. In addition, it is likely thatexon ４. Furthermore, subsequent studies have shown

many genes for hypospadias remain to be identified.

the loss of CXorf6 in all patients with myotubular

We have recently shown that CXorf6（chromosome

myopathy and ４
６, XY DSD（Bartsch et al., １
９
９
９；JL,

X open reading frame ６）is a novel gene for hypo-

unpublished observation）, and no other candidate

spadias［３］, and coined a new gene symbol MAMLD

gene for ４
６, XY DSD has been identified within the1（mastermind-like domain containing, １）, on the basis

commonly deleted region. These findings imply thatof its characteristic protein structure（see below）［４］.

CXorf6 is an excellent candidate gene for ４
６, XY

Here,

DSD, especially hypospadias.

wereview

thecurrent

knowledge

about

MAMLD1.

Identification of pathologic CXorf 6 mutations
Cloning of a candidate gene for ４６, XY DSD

in hypospadiac patients

A gene for ４
６, XY DSD has been postulated

We performed direct sequencing for the coding ex-around MTM1 for myotubular myopathy on Xq２
８, on

ons ３―６ and their flanking splice sites of CXorf6 in

the basis of the finding that genital development is１
６
６ patients with various types of ４６, XY DSD（１５２normal in patients with intragenic MTM1 mutations,sporadic cases and １
４ probands of familial cases）
.
The １
６
６ patients consisted of １
１
７ Japanese patients

Correspondence : Yuka WADA Department of Endocrinology and Metabolism, National Reserarch Institute forChild Health and Development, Tokyo, Japan
TEL :０
３―３
４
１
６―０
１
８
１
FAX :０
３―５
４
９
４―７
０
２
６
E-mail : ywada@nch.go.jp（１
１
３ sporadic cases and four probands of familial
cases）,４
５ European patients（３９ sporadic cases andsix probands of familial cases）, and four Chinese patients（four probands of familial cases）. The １
１
７ Japa-Japanese Journal of Reproductive Endocrinology（2008）13 : 37-42

37

Yuka WADA et al.

Fig. １．Molecular findings in patients with nonsense mutations.
Ａ．The pedigrees and electrochromatograms of Japanese patients with nonsense mutations（Ａ-Ｃ）. The black squares indicate the patients with ４
６, XY DSD and the mutant CXorf 6 , and the circles with dots represent molecularly confirmed carrier females. The asterisks in the chromatograms indicate the mutant and the corresponding wildtype nucleotides. N.E. : not examined.
Ｂ．The NMD analysis. Upper part : The black and gray boxes represent the coding regions, and the open boxes denote the untranslated regions. The positions of the mutations and variations are shown. RT-PCR for the two regions（RT-PCR-１and-２）has produced
no bands after ３
０ cycles and very faint bands after ４
０ cycles in cases１-４. Lowe part : NMR analysis in case ４ with and without an
NMD inhibitor cycloheximide（CHX）. After ４０ cycles of RT-PCR for the region １, no band is seen without cycloheximide（CHX）treatment, and a clear band is delineated with CHX treatment.

nese patients comprised １
９ cases with gonadal dys-of their positions ［１０］. Consistent with this, RT-PCR

genesis（１０ with complete type and ９ with incomplete

for leukocytes indicated drastically reduced transcriptstype）with no demonstrable mutation in the known or. Furthermore, the NMD
in the cases １―４（Fig. １B）

candidate sex determining genes SRY, DMRT1, SF1

was protected by an NMD inhibitor cycloheximide,(alias AD4BP) , and LHX9［２］, two cases with ４
６, XY

providing further support for the occurrence of NMD

DSD with feminized genitalia of unknown cause, ５
６

in the three nonsense mutations［３，４］.

cases with hypospadias（１６ with glandular type, １
６with penile type, ２０ with penoscrotal type, and ４

Clinical findings in mutation positive patientswith perineal type）, and ４０ cases with isolated cryptorchidism（３３ with unilateral inguinal or abdominal
type and seven with bilateral inguinal type）.
Consequently, three nonsense mutations were iden-

The cases １―４ had penoscrotal hypospadias withchordee as the conspicuous genital phenotype, in association

with

other

phenotypes（Table１）.

Pituitary-gonadal

maternally related half brothers from family A（cases

within the normal range, including the human chori-

１ and ２）, Q１
９７X in a patient from family B（case ３）,

onic gonadotropin（hCG）-stimulated testosterone value

and R６
５
３X in a patient from family C（case ４）（Fig.

in the case １ at two years and five months of age,

１A）
［３］
. The mothers of families A and C were het-

and the basal testosterone values in the case ２ aterozygous for the mutations, although the mother of

one month of age and in the case ４ at three months

family B was not studied. These mutations were ab-of age when serum testosterone is physiologically ele-

sent in １
５０ Japanese control males. In addition to thevated. Thus, the diagnosis of idiopathic hypospadias

three nonsense mutations, we also found three appar-

was initially made in the cases １―４. It was suspected

ently non-pathologic variants : P２
８
６S and Q５０
７R thatthat testosterone production was compromised only

were not co-segregeated with the ４６, XY DSD in af-

during fetal life, or that external genitalia had defec-

fected families, and a previously reported polymor-

tive development of anlagen or impaired responsive-phism N５８９S（rs２０
７
３
０
４３）. In addition, direct sequenc-

ness

ing confirmed lack of a mutation in AR and SRD5A2

could also affect male genital development by attenu-

in cases １―４.

to

serum

genitaltified in Japanese patients with hypospadias : E１
２
４X in

testosterone.

hormoneWhilevaluesplacental

remained

dysfunction

ating the production of human chorionic gonadotropin

The three nonsense mutations are predicted to［２］, there was no pregnant episode suggestive of pla-

cause nonsense mediated mRNA decay（NMD）because

cental dysfunction. The three mothers experienced

38

Japanese Journal of Reproductive Endocrinology Vol.13 2008

MAMLD１（CXorf６）: A New Gene for Hypospadias

Table １ Clinical findings of the four Japanese cases with CXorf6 nonsense mutations
Patient

Case １Case ２

Case ３

Case ４<Genital findings>
Age at exam.（yr : mo）
Clinical diagnosis
Urethral meatus
Urethroplasty
Penile length（cm）
Testis size（mL）
Testis position
Orchidopexy
Scrotal appearance
Wolffian structures
Müllerian structures
Renal structures

０：０
４
Hypospadias with chordee
Penoscrotal junction
２．
５uyr
２．
５（−１．
５ SD）
１−２（B）（WNR）
Inguinal（B）
６．
３ yr
Bifid and hypoplastic
Normal on MRI
Absent on MRI
Normal on MRI<Serum hormone values>
Age at exam.（yr : mo）
LH（IU/L）
FSH（IU/L）
Testosterone（nmol/L）
DHT（nmol/L）

０：０
４
１．
２（０．
１−４．
７）
１．
５（０．
４−５．
７）
a
１．
４（０．
１−１
２．
０）→９．
０（７．
０−１
５．
０）
a
０．
８（０．
２−４．
５）→３．
７

０：０
１
３．
１（０．
１− ４．
７）
２．
２（０．
４− ５．
７）
９．
０（４．
０−１
４．
０）
１．
２（０．
２− ４．
５）

２：０
０
０．
２（＜０．
２−３．
１）
１．
６（０．
２−５．
２）
０．
１（０．
１−１．
０）
N.E.

０：０
３
N.E.
N.E.
９．
４（４．
０−１
４．
０）
N.E.

Age at exam.（yr : mo）
LH（IU/L）
FSH（IU/L）
Testosterone（nmol/L）
DHT（nmol/L）

２：０
５
b
０．
２（＜０．
２−３．
１）→３．
５（１．
４−６．
０）
＜０．
２（０．
２−５．
２）→１．
５（２．
３−６．
９）b
＜０．
３
（０．
１−１．
０）→１
０．
１
（７．
０−１
５．
０）a
０．
０
７（０．
０
５−２．
０）→２．
８
４a

２：０
５
０．
２（＜０．
２−３．
１）
０．
８（０．
２−５．
２）
０．
７（０．
１−１．
０）
＜０．
１
５（０．
０
５−２．
０）

４：０
０
＜０．
２（＜０．
２−１．
２）
１．
６（０．
７−３．
０）
＜０．
３（＜０．
５）
N.E.

６：０
３
０．
２（＜０．
２−１．
４）
１．
２（０．
３−４．
０）
０．
３（＜０．
５）
N.E.

０：０
１
２：０
０
０：０
１
Hypospadias with chordee Hypospadias with chordee Hypospadias with chordee
Penoscrotal junction
Penoscrotal junction
Penoscrotal junction
３．
９ yr
６．
０ and ６．
６ yr
１．
９ yr
２．
５（−１．
５ SD）
２．
０（−３．
４ SD）
１．
２（−３．
５ SD）
１−２（B）
（WNR）
１（B）
（WNR）
１−２（B）（WNR）
ScrotalScrotalRetractile（B）
…
…
１．
９ yr
Bifid
Bifid
Bifid
Normal on MRI
N.E.
N.E.
Absent on MRI
N.E.
N.E.
Normal on MRI
Normal on ultrasounds
N.E.

Abbreviations. SD : standard deviation ; N. E. : not examined ; B : bilateral ; MRI : magnetic resonance imaging ; WNR : within the normal
range（１―２ mL before puberty）；N.D. : not determined ; LH : luteinizing hormone ; FSH : follicle stimulating hormone : and DHT : dihydrotestosterone
Assessment of body sizes（length, height, weight, and head circumference）, penile length, testis size, and menarchial age is based on theJapanese reference data.
The hormone values in parentheses represent the age-and sex-matched normal range in the Japanese ; the reference data for serum hormones have been based on the literature.
ab

After a human chorionic gonadotropin stimulation（３０００ IU/m２/dose i.m. for three consecutive days ; blood sampling on day ４）.
Peak values during a gonadotropin releasing hormone test（１００µg/m２ bolus i.v. ; blood sampling at ０, ３
０, ６
０, ９
０, and １
２
０ min）.

menarche at １
２―１
３ years of age and had regular cy-

dig cells. In extragonadal tissues at E１
２．
５, m-CXorf6

cles at ３５, ３
７, and ３
８ years of age, respectively.

expression was absent in the adrenals and weakly
and diffusely identified in the external genital region

Expression pattern

including the genital tubercle at a level similar to that
detected in the neighboring extragenital tissues（Fig.２

PCR-based human cDNA library screening has re-B）. m-CXorf6

was also clearly expressed in thevealed ubiquitous expression of CXorf6 with and with-

Müllerian ducts, forebrain, somite, neural tube, andout exon ４（∆Exon ４）［３］. Exon ４ positive splice vari-pancreas. In the postnatal testis, m-CXorf6 expression

ant was more strongly expressed than ∆Exon ４.

was weakly identified within the cords until one week

In situ hybridization（ISH）analysis for the murineof age and became faint thereafter. In the postnatal

homologous gene（G630014P10Rik, here described as

ovary, m-CXorf6 expression was barely detected until

m-CXorf6 for convenience）showed cell type-specific ex-

two weeks of age and clearly identified in granulosa

pression pattern［３］. Namely, m-CXorf6 is specifically

cells at the perifollicular regions of most Graafian fol-and transiently expressed in Sertoli and Leydig cells

licles at ３ and ８ weeks of age.

around the critical period for sex development（E１２．
５These data imply that nonsense mutations of CXorf-E１４．
５）（Fig. ２A）. This expression pattern has been

6 cause hypospadias primarily because of transientconfirmed by double staining with antibodies for Ad４

testicular dysfunction and resultant compromised tes-bp/Sf-１ that serves as a marker for Sertoli and Ley-

tosterone production around the critical period for sex

RESEARCH FRONTIER

39

Yuka WADA et al.

tion［４］. These findings suggest that CXorf6 is regulated by Ad4bp/Sf-1.

Function of m-CXorf6 in testosterone
production
We performed knockdown analysis with siRNAs for
m-CXorf6, using mouse Leydig tumor（MLT）cells thatretain the capability of testosterone production andthe responsiveness to hCG［４］. When the mRNA levelof endogenous m-CXorf6 was severely reduced in theFig. ２． In situ hybridization analysis of the murine homolog for
CXorf6(m-CXorf6) .
Ａ．Expression patterns in the fetal testes at E１
２．
５ and E
１
４．
５. The blue signals are derived from in situ hybridization for m-CXorf6 , and the brown signals from immunohistochemical staining with Sf１（Ad４bp）antibodies. m :mesonephros ; G : germ cell ; S : Sertoli cell ; and L :Leydig cell. The scale bars in the low and high power
fields represent ２００ µm and ２
０ µm, respectively.
Ｂ．Expression patterns in the fetal adrenal（upper part）andexternal genitalia（lower part）of male mouse at E１
２．
５.
m : mesonephros ; g ; gonad ; ad : adrenal ; and GT :genital tubercle（the between two arrows）. CXorf6 is not
expressed in the adrenal, and weakly and diffusely expressed in the external genitalia as in other non-genitalskin tissues.

０％）, testosterone promouse Leydig tumor cells（２５―３０％ after ４
８ hours ofduction was decreased to ５
０―６
incubation and one hour after hCG stimulation. Thisimplies that CXorf6 is involved in the testosterone
biosynthesis. Furthermore, since testosterone production would probably be attenuated rather than abolished in the absence of CXorf6, this is consistent
with the hypospadias phenotype in the affected patients［２］.

Functional studies of CXorf６ protein
We found that CXorf６ protein has a unique struc-development. The data also explain why postnatal en-

ture with homology to that of mastermind like ２

docrine data were normal in the cases １―４. Further-（MAML２）（alias, Mam-３）
protein（Fig. ３A）
［４］
. A uniquemore, from the expression patterns in the adult testes

amino acid sequence, which we designate mastermindand ovaries, it is worth examining whether spermato--like（MAML）motif, was inferred from sequence align-

genic function can be preserved in CXorf6 mutation

ment with MAML１, MAML２, and MAML３ proteins

positive patients, and whether CXorf6 is involved in

［１
４，
１
５］
. The MAML motif was well conserved among

the adult ovarian function.

CXorf６ orthologs identified in frog, bird, and mammals. In addition, a glutamine-rich, a proline-rich, andSF-１ target sequence in CXorf6

a serine-rich domains were identified in CXorf6.
MAML2 is a non-DNA binding transcriptional co-

Mouse CXorf6 is co-expressed with Ad4bp/Sf-1, andactivator in Notch signaling［１４，１５］that plays an im-

SF-1 is known to regulate multiple genes involved in

portant role in cell differentiation in multiple tissues

sex development, by binding to specific DNA se-by exerting either inductive or inhibiting effects ac-

３］. This implies that CXorf6 is also
quences ［１１―１

cording to the context of the cells［１６］. Upon ligand-controlled by Ad4bp/Sf-1. Consistent with this notion,

receptor interaction, Notch intracellular domain（N-CXorf6 harbors a putative SF-１ binding sequence

ICD）is translocated from the cell surface to the nu-“CCAAGGTCA” at intron ２ in the upstream of thecleus and interacts with a DNA-binding transcription

coding region. This binding site also resides at intron

factor, recombination signal binding protein-J（RBP-J）,

１ in the upstream of the coding region of the m-to activate target genes like hairy/enhancer of split １

CXorf6. Furthermore, we performed DNA binding and（Hes1）and Hes5［１７］. In this canonical Notch signal-

luciferase assays, showing that SF-１ binds to the puta-

ing process, MAML２ forms a ternary complex with Ntive target sequence and exert a transactivation func--ICD and RBP-J at nuclear bodies, enhancing the tran-

40

Japanese Journal of Reproductive Endocrinology Vol.13 2008

MAMLD１（CXorf６）: A New Gene for Hypospadias

Fig. ３．Functional studies of the wildtype CXorf６ protein.
A. Protein structure analysis. The structure of human CXorf６ and MAML２ proteins. The identified domains are shown, together with thepositions of the three nonsense mutations.
B. Subcellular localization analysis, showing co-localization of the wildtype CXorf６ and MAML２ in the nuclear bodies.
C. Transactivation functions for the promoter of Hes3 . The（＋）symbols indicate the presence of expression vectors with cDNAs for
CXorf6 , MAML2 , N１-ICD（Notch １ intracellular domain）, and N２-ICD（Notch ２ intracellular domain）, whereas the（−）symbols denotethe presence of expression vector only（empty）.

scription of the Notch target genes［１
４，１
５，１
８―２
０］
.

results argue that CXorf6 exerts its transactivation ac-

In addition to such canonical Notch target genes, re-tivity independently of RBP-J binding sites.

cent studies have shown that Hes3 can be induced

Furthermore, the E１
２
４X and Q１
９
７X proteins hadby stimulation with a Notch ligand, via a STAT３（sig-no transactivation function, whereas the R６
５
３X protein

nal transducer and activator of transcription３）mediatedas well as the three variant（P２８６S, Q５０
７R, and N５８９pathway［２１］. This finding, together with lack of Hes

S）proteins retained a nearly normal transactivating ac-

3 induction by N-ICD［２２］, implies that Hes3 repre-

tivity. In addition, the transactivation function was sig-

sents a target gene of a non-canonical Notch signal-

nificantly reduced in the L１
０
３P protein（an artificiallying.

constructed variant affecting the MAML motif）and

Thus, we first examined whether CXorf６ localizes

normal in the ∆Exon ４. These findings suggest thatto the nuclear bodies, as observed for MAML２［４］.

the E１
２
４X and Q１
９
７X proteins have no transactivation

CXorf６（wildtype with exon ４）was distributed in afunction, and that R６
５
３X protein, when it is artificiallyspeckled pattern and co-localized with the MAML２

produced, has a normal transactivating activity, al-protein（Fig. ３B）. Furthermore, while the E１
２
４X andthough R６
５
３X as well as E１
２
４X and Q１
９
７X under-Q１
９
７X fusion proteins resided in the nucleus, theygoes NMD in vivo.

were incapable of localizing to the nuclear bodies.

However, CXorf6 is unlikely to have DNA-binding

The R６
５
３X and apparently non-pathologic missense

activity［４］, so that it remains to be clarified how

proteins showed a punctate pattern, and co-localized

CXorf6 transactivates Hes3. It also remains to be de-with the wildtype CXorf６.

termined whether transactivation for Hes3 also takes

Next, we studied whether CXorf6 has a transactivation function for Notch targets using luciferase re-place in vivo, and is involved in testosterone production.

porter assays［４］. Although CXorf6 was incapable ofenhancing the promoter activities of the canonicalConclusions and perspectives

Notch target genes Hes1 and Hes5 with the RBP-J
binding site 睇, CXorf6 transactivated the promoter ac-

MAMLD1(CXorf6) is a causative gene for hypo-tivity of the non-canonical Notch target gene Hes3

spadias, and possibly other forms of ４６, XY DSD.

without the RBP-J binding site（Fig. ３C）［２
２］. TheseMAMLD1(CXorf6) appears to play a supportive role in

RESEARCH FRONTIER

41

Yuka WADA et al.

the testosterone production around the critical period
for sex development. MAMLD１（CXorf６）protein localizes to the nuclear bodies and has a transactivation
function for Hes3 at least in vitro.
However, several matters remain to be clarified.
They include：盧 the prevalence of MAMLD1(CXorf6)
mutations in hypospadias and other ４
６, XY DSD；盪
the involvement of MAMLD1(CXorf6) in spermatogenic
function and ovarian function；蘯 MAMLD1(CXorf6)
dependent molecular network involved in testosterone
production ; and盻 the molecular relevance of MAMLD
1(CXorf6) to Notch signaling. Further studies including knockout mouse experiments, are necessary to resolve these matters.

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